COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING NEURODEGENERATIVE DISEASE

RELATED PATENT APPLICATIONS

[0001] This patent application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 62/335,674 filed on May 12, 2016. The entire content of the foregoing application is incorporated herein by reference, including all text, tables and drawings.

FIELD OF INVENTION

[0002] Technology provided herein relates in part to compositions, devices and methods for diagnosing and treating neurodegenerative diseases and disorders.

BACKGROUND OF THE INVENTION

[0003] Neurodegenerative diseases are becoming increasingly prevalent in the world population. These diseases involve the degeneration and death of cells of the nervous systems and brain, resulting in a variety of symptoms including loss of motor and brain function. Included among neurodegenerative diseases are Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease.

[0004] While much effort and research has been dedicated to understanding neurodegenerative diseases and developing treatments, to date no long-term effective treatment exists. BRIEF SUMMARY OF THE INVENTION

[0005] Much of the research and many novel therapeutics in the field of

neurodegenerative disease has been focused on reducing the aggregation of self-proteins that result in the formation of protein plaques and tangles that are believed to result in the development of neurodegenerative disease and associated symptoms. For example, Alzheimer's disease has been found to involve the formation of beta amyloid plaques and neurofibrillary tangles, respectively.

[0006] The present inventors have surprisingly discovered that the immune system plays a role in the development of neurodegenerative disease and associated symptoms. The present inventors have found that there is a modified immune response in subjects with neurodegenerative disease. Without being limited to any particular theory, the formation of protein plaques and tangles may trigger the immune system to recognize and become reactive to proteins that normally would not activate an immune response. As a result, the immune system is primed to react to the self-antigens and launches an autoimmune response against these self-antigens that results in inflammation and other downstream effects leading to the development and/or progression of neurodegenerative disease and resulting symptoms. Thus, the present inventors have discovered that targeting, preventing and/or reprogramming the immune response to self-antigens is a key component to treatment of neurodegenerative diseases.

[0007] The present inventors have also identified proteins and peptides that elicit an immune response in neurodegenerative diseases, including HLA binding peptides (T cell epitopes) that elicit an immune response and that can be used individually or in combination in the methods and compositions described herein. These proteins and peptides can also be used in methods for diagnosing neurodegenerative diseases and methods for profiling immune responses in a subject, including identifying the proteins or peptides that have elicited or that will elicit an immune response in a subject, such as a subject with or at risk of developing a neurodegenerative disease.

[0008] Thus, in one aspect there is presently provided, a method of determining whether a subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease or disorder comprising determining whether the subject has a modulated immune response wherein a modulated immune response indicates that the subject has, is at risk of having, or is in need of treatment for the neurodegenerative disease.

[0009] In another aspect, there is provided a method of determining whether a subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease or disorder, the method comprising obtaining a biological sample from the subject, measuring an immune response in the sample and comparing the immune response in the biological sample from the subject to the immune response in a control biological sample, wherein a modulated immune response in the biological sample from the subject when compared to the control biological sample indicates that the subject has, is at risk of having, or is in need of treatment for the neurodegenerative disease.

[0010] In certain embodiments, the method comprises determining the subject's immune response to one or more proteins or peptides of the central nervous system, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the method comprises

determining the subject's immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0011] In some embodiments, the method comprises determining whether the subject has one or more of a modulated macrophage, monocyte, dendritic cell, T cell, B cell, immune mediator and cytokine response. In different embodiments, the method comprises detecting a modulated innate immune response or a modulated adaptive immune response. In particular embodiments, the method comprises detecting a modulated immune response specific to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0012] In certain embodiments, the method comprises determining whether the subject has a modulated T cell response comprising one or more of stimulation of T cells, proliferation of T cells, differentiation of T cells, increased or decreased number of T cells and modulated activity of T cells and the T cell response may be to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. The modulated T cell response may be measured by contacting the biological sample from the subject with one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof to determine the level of T cell response in the biological sample from the subject and comparing the level of T cell response in the biological sample to a control biological sample.

[0013] In other embodiments, the method comprises determining whether the subject has a modulated B cell response comprises one or more of stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells and the B cell response may be to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In particular embodiments, the method comprises detecting autoantibodies or B cells generating autoantibodies, including but not limited to autoantibodies to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. The modulated B cell response may be measured by contacting the biological sample from the subject with one or more of the proteins listed in Table 1 or 2, one or more peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof to determine the level of B cell response in the biological sample from the subject and comparing the level of B cell response in the biological sample to a control biological sample.

[0014] In further embodiments, the method comprises determining whether the subject has a modulated cytokine response is measured by contacting the biological sample from the subject with antibodies that bind one or more cytokines.

[0015] In still further embodiments, the method comprises detecting an immune complex. In certain embodiments, the immune complex comprises one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0016] In particular embodiments, the method comprises contacting the biological sample with a composition comprising one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0017] In other embodiments, the modulated immune response is measured by contacting the biological sample from the subject with an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or contacting the biological sample from the subject with a multimer comprising a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, wherein the multimer binds immune cells in the subject.

[0018] In some embodiments, the method determines that the subject has, is at risk of having, or is in need of treatment for Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease or designates the subject for treatment of one or more of Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease. [0019] In some embodiments, the method comprises isolating the biological sample from the subject, for example prior to or after the development of the neurodegenerative disease.

[0020] In another aspect, there is provided a method of determining whether a subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease, the method comprising administering to the subject an agent that can detect a modulated immune response in the subject. In certain embodiments, the method comprises administering to the subject a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and may comprise detecting binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject. In other embodiments, the method comprises administering to the subject an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject. In still other embodiments, the method comprises administering to the subject a multimer comprising a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0021] In yet another aspect, there is provided a diagnostic kit for determining whether a subject has, is at risk of having, or is in need of treatment for a

neurodegenerative disease, the kit comprising one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds to one or more of the proteins listed in Table 1 or 2 or one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. The diagnostic kit may further comprise antibodies that bind one or more cytokines. [0022] In a further aspect, there is provided a diagnostic kit comprising reagents for detecting an immune complex, wherein the kit comprises a first reagent that binds to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, in the immune complex and a second reagent that binds to an antibody that binds the one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of the immune complex.

[0023] In an another aspect, there is provided a method of treating a

neurodegenerative disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.

[0024] In still a further aspect, there is provided a method of treating a

neurodegenerative disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response to one or more proteins or peptide of the central nervous system, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0025] In another aspect, there is provided, a method of treating a neurodegenerative disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0026] In certain embodiments, the present invention provides methods of treatment comprising modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting an innate immune response, such as an adaptive immune response, including but not limited to an adaptive immune response that is specific to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0027] In certain embodiments, the agent comprises a protein or peptide, including but not limited to one or more of the proteins listed in Table 1 or 2, or a modification, subsequence, homologue, variant or derivative thereof or one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments, the agent is a recombinant protein or peptide, a small molecule, a multimer, ligand mimetic, nucleic acid or an antibody, a Fab fragment or other antibody derivative, including but not limited to an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification

subsequence, homologue, variant or derivative thereof. In other embodiments, the agent is a pharmaceutical composition for the treatment of inflammatory or immune disorders, including but not limited to an anti-T F agent, anti-cytokine agent, statin, anti- chemokines, anti-integrins or flavonoid, for example Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Ezetimibe/simvastatin, Pitavastatin, Cerivastatin, Mevastatin, Atorvastatin/amlodipine, Niacin/simvastatin, Niacin/lovastatin, Simvastatin/sitagliptin, 3,6'-dithiothalidomide, Enzogenol, Tocilizumab, Rituximab, Ofatumumab, Belimumab, Epratuzumab, Abatacept, Golimumab, Certolizumab, Sifalimumab, Intravenous immunoglobulin, Glatiramer acetate, Natalizumab, Infliximab, Enbrel, Humira,

Eculizuma, Ixekizumab, Brodalumab, Secukinumab, Ustekinumab, AMG 811,

Alemtuzumab, Dimethyl fumarate, fingolimod, ocrelizumab, ofatumumab, Anakinra, canakinumab, rilonocept, Rapamycin, cyclosporine, tofactinib, tubastatin, prednisone, methyltrexate, Medrol, hydrocortisone, veripred, celestone souluspan and kenalog.

[0028] In certain embodiments, the method comprises administering to the subject two or more agents that modulate, inhibit, block, decrease, increase, enhance, promote or elicit an acute or chronic immune response. In particular embodiments, the method comprises agents selected from two or more of the group consisting of a protein, a peptide, antibody, small molecule, multimer, antibody, antibody derivative, ligand mimetic, nucleic acid and pharmaceutical composition for the treatment of inflammatory or immune disorders in combination. In certain embodiments, the two or more agents are conjugated.

[0029] In particular embodiments, the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a B cell response to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the B cell response comprises one or more of stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells. IN certain embodiments, the agent modulates the activity, proliferation or activation of B cells generating autoantibodies, including but not limited to

autoantibodies to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0030] In other embodiments, the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a T cell response to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, wherein the T cell response comprises one or more of stimulation of T cells, proliferation of T cells, differentiation of T cells, increased or decreased number of T cells and modulated activity of T cells.

[0031] In still other embodiments, the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a cytokine response to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0032] In certain embodiments, the method comprises depleting B cells in the subject, including but not limited to autoreactive B cells, for example B cells specific for one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0033] In other embodiments, the method comprises depleting T cells in the subject, including but not limited to autoreactive T cells, for example T cells specific for one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0034] In particular embodiments, the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting the expression or activity of mediators of immune cell activity, such as cytokines, immune activators, chemokines, growth factors or TNF family members, for example AREG, Granzyme, Histamine, IFNa/b, IFNg, IL12, IL15, IL16, IL17a-f, ILlb, 112, IL21, IL22, IL23, IL25, IL27, GM-CSF, IL33, IL4, IL5, IL6, IL7, IL8, IL9, LFA-1, LIF, lymphotoxin, Mac-1, MCP-1, MlPla, Perforin, TGF-B, TNFa, VLA-4, CCLl, CCLl l, CLL17, CCLl, CCL20, CCL22, CCL3, CCL4, CCL5, CXCLIO, CXCL13, CXCL8, RANTES, CXCL12, G-CSF, M-CSF, VEGF, PDGF, 4-lBB, APRIL, BAFF, CD27, CD30, CD30L, CD70, DR3, DR4, DR5, FAS, FASL, GITR, HVEM, LIGHT, LTB, OX40, Ox40L, TACI, TRAIL,

TWEAK, IL11, IL14 or IL10.

[0035] In particular embodiments, the agent modulates, inhibits, blocks or decreases binding of an autoantibody to one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0036] In different embodiments, the method comprises administering the agent to the subject prior to or after the onset of the neurodegenerative disease. In certain embodiments, the method comprises treating the subject for Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease. In certain

embodiments, the method comprises treating a symptom of the neurodegenerative disease.

[0037] In a further aspect, there is provided a pharmaceutical composition comprising an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0038] In still a further aspect, there is provided a pharmaceutical composition comprising one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[0039] In yet another aspect, there is provided a method of determining the efficacy of a treatment for a neurodegenerative disease in a subject, the method comprising obtaining a biological sample from the subject following administration of the treatment, measuring an immune response in the subject and comparing the immune response in the biological sample from the subject to the immune response in a control biological sample, wherein a modulated immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the neurodegenerative disease. In certain embodiments, a reduced immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the

neurodegenerative disease. In certain embodiments, the control biological sample is a biological sample taken from the subject prior to treatment. In particular embodiments, the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In different embodiments, the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, immune cell mediator or cytokine response.

[0040] In another aspect, there is provided a method of determining the efficacy of a treatment for a neurodegenerative disease or disorder in a subject, the method comprising administering to the subject an agent that can detect a modulation in the immune response in the subject after the treatment from the immune response in the subject prior to treatment. In certain embodiments, the method comprises administering to the subject after treatment a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof. In some embodiments, the method comprises detecting binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein a decrease in the amount of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject when compared to the amount of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease or disorder.

[0041] In another embodiment, the method comprises administering to the subject after treatment an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject, wherein a decrease in the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject when compared to the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a

subsequence, homologue, variant or derivative thereof in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease or disorder.

[0042] In yet another embodiment, the method comprises administering to the subject after treatment a multimer comprising a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof wherein a decrease in the amount of T cells that bind the multimer in the subject after treatment when compares to the amount of T cells that bind the multimer in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease or disorder.

[0043] In different embodiments, the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, immune cell mediator or cytokine response.

[0044] In a further aspect, there is provided a method of determining an appropriate treatment for a subject to be treated for a neurodegenerative disease or disorder, the method comprising determining the subject's immune response to one or more proteins or peptides of the central nervous system, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, wherein detection of an immune response to a protein or peptide of the central nervous system, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, indicates that the subject should be treated by modulating the immune response to that protein or peptide, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0045] In certain embodiment, the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, wherein detection of an immune response to a protein listed in Table 1 or 2, a peptide listed in any of Tables 3 to 102, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, indicates that the subject should be treated by modulating the immune response to that protein or peptide, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0046] In certain embodiments, the method comprises obtaining a biological sample from the subject, measuring an immune response in the sample to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, wherein detection of an immune response in the sample to a protein listed in Table 1 or 2, a peptide listed in any of Tables 3 to 102, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, indicates that the subject should be treated by modulating the immune response to that protein or peptide, or modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[0047] In yet another aspect, there is provided a method of determining an appropriate treatment for a subject to be treated for a neurodegenerative disease or disorder, the method comprising administering to the subject an agent that can detect a modulated immune response in the subject. In different embodiments, the method comprises administering (1) a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein detection of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject determines that the subject should be treated by modulating the immune response to the modified form of the one or more the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof; (2) an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject wherein detection of binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof determines that the subject should be treated by modulating the immune response to the modified form of the one or more the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof; or (3) a multimer comprising a peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof, and detecting binding of the multimer to a T cell in the subject, wherein detection of binding of the multimer to a T cell in the subject determines that the subject should be treated by modulating the immune response to the peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof, or a protein comprising the peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions [0049] The terms "dose" and "dosage" are used interchangeably herein. A dose refers to the amount of active ingredient given to an individual at each administration. For the present methods and compositions provided herein, the dose may generally refer to the amount of condition or disease (e.g. neurodegenerative disease or disorder) treatment, neurodegenerative disease or disorder agent, neurodegenerative disease or disorder therapeutic agent, inflammatory or autoimmune disease treatment, inflammatory or autoimmune disease therapeutic agent, immune response agonist, immune response antagonist, antibody, antibody fragment, protein, peptide, T cell agonist, T cell antagonist, B cell agonist, B cell antagonist, cytokine agonist, cytokine antagonist, antiinflammatory, anti-TNF agent, statin, anti-chemokines, anti-integrins or flavonoid. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of administration; size and tolerance of the individual;

severity of the condition; risk of side effects; and the route of administration. One of skill will recognize that the dose can be modified depending on the above factors or based on therapeutic progress. The term "dosage form" refers to the particular format of the pharmaceutical or pharmaceutical composition, and depends on the route of

administration. For example, a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.

[0050] The terms "subject," "patient," "individual," etc. are not intended to be limiting and can be generally interchanged. That is, an individual described as a

"patient" does not necessarily have a given disease, but may be merely seeking medical advice.

[0051] "Biological sample" or "sample" includes but is not limited to bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, immune cells, macrophages, T cells, B cells, monocytes, dendritic cells etc. A biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, Mouse; rabbit; or a bird; reptile; or fish. [0052] A "standard control", "control" or "control biological sample" refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a subject biological sample, test sample, measurement, or value. For example, a test biological sample can be taken from a patient suspected of having a neurodegenerative disease and compared to samples from a known patient with a neurodegenerative disease or a known normal individual without a neurodegenerative disease. A standard control can also represent an average measurement or value gathered from a population of similar individuals that do or do not have a given disease or condition (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc. that do not have a neurodegenerative disease. A standard control value can also be obtained from the same individual, e.g., from an earlier-obtained sample, prior to disease or condition (e.g. neurodegenerative disease), or prior to treatment. One of skill will recognize that standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, individual, specific cell types, specific bodily fluids, specific tissues, T cells, B cells, microglia, macrophages, cytokines, etc.).

[0053] One of skill in the art will understand which standard controls are valuable in a given situation and be able to analyse data based on comparisons to standard control values. Standard controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0054] As used herein "antigen" refers to any protein, peptide, biological component, molecule or compound that induces an immune response.

[0055] As used herein "autoantibody" refers to an antibody that is generated against a "self antigen", that is an antigen (e.g. protein or peptide) that is expressed by the host or subject as opposed to an antigen from a foreign source (e.g. virus, bacteria).

[0056] As used herein and understood by a person of skill in the art, "autoreactive" refers to a cell that recognizes or is reactive to a self-antigen. Thus an autoreactive B cell is a B cell that recognizes and is reactive to or stimulated by a self-antigen. An autoreactive T cell is a T cell that recognizes and is reactive to or stimulated by a self- antigen.

[0057] As used herein "innate immune response" means a non-specific immune response to an antigen that does not result in immune memory for that antigen in the subject.

[0058] In certain embodiments of the present invention, the method comprises measuring the innate immune response of a subject to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, or protein plaques or tangles comprising the same. In particular embodiments, the innate immune response is to one or more of the proteins listed in Table 1 or 2, or a

modification, subsequence, homologue, variant or derivative thereof or one or more of the peptides listed in Tables 3-102 or a modification, subsequence, homologue, variant or derivative thereof.

[0059] As used herein, "adaptive immune response" includes a naive or recall immune response that is specific to a particular antigen and that results in the

establishment of immune memory to the antigen. A "recall response," "recall immune response," "memory response," "memory immune response" and grammatical variations thereof means an immune response to an antigen to which a subject has previously been exposed. A recall or memory response is therefore an immune response subsequent to the initial antigen exposure and immune response. For example, a recall response may occur following exposure of the subject to the antigen for a second (secondary), third (tertiary), fourth, fifth, sixth, seventh, eighth, ninth, tenth, or any subsequent antigen exposure.

[0060] A recall or memory response is distinguished from a primary response to an antigen; a primary response is an immune response that occurs when a subject is exposed to an antigen for the first time. In a primary response, naive T cells expand. In contrast, recall immune responses are believed to be attributed to reactivation of long-lived, antigen-primed T lymphocytes that arise from differentiated effector T cells in a quiescent state. Thus, a "recall response" is an immune response in which antigen-primed cells participate. Recall immune responses can result in undesirable or adverse symptoms and physiological complications, such as inflammation.

[0061] In certain embodiments of the present invention, the method comprises measuring or modulating the adaptive or recall immune response of a subject, for example, the adaptive or recall immune response of a subject to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, or protein plaques or tangles comprising the same. In particular embodiments, the recall immune response is to one or more of the proteins listed in Table 1 or 2, or a modification, subsequence, homologue, variant or derivative thereof or one or more of the peptides listed in Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof.

[0062] As used herein, the terms "treatment", "treat" and "prevent" may refer to any delay in onset, reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort or function, decrease in the occurrence of a given condition or disease or condition or disease symptoms in a patient, decrease in severity of the condition or disease state etc. The effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient prior to, or after cessation of, treatment. As indicated above, treatment may be complete (no detectable symptoms) or partial, for example that fewer, less severe or less frequent symptoms are observed than would likely occur absent treatment.

[0063] "Therapeutically effective dose or amount" as used herein means a dose that produces effects for which it is administered (e.g. treating or preventing a.

neurodegenerative disease or disorder ). The exact dose and formulation will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003), and Pickar, Dosage Calculations (1999)). For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as "-fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a standard control. A therapeutically effective dose or amount may ameliorate one or more symptoms of a disease. A therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.

[0064] The term "diagnosis" refers to a relative probability that a disease or condition (e.g. neurodegenerative disease or disorder) is present in the subject. Similarly, the term "prognosis" refers to a relative probability that a certain future outcome may occur in the subject with respect to a disease state. For example, in the context of the present invention, prognosis can refer to the likelihood that an individual will develop a neurodegenerative disease or disorder (e.g. Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease) or the likely severity of the disease (e.g., duration of disease). The terms are not intended to be absolute, as will be appreciated by any one of skill in the field of medical diagnostics.

[0065] The terms "correlating" and "associated," and "determining" in reference to the measurement and/or analysis of a disease or condition (e.g. Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease) risk factor, refers to comparing the presence or amount of the risk factor (e.g. modulation in response to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, or protein plaques or tangles comprising the same, amount of autoantibodies, amount of autoreactive immune cells, number of B cells or T cells; B and/or T cell stimulation, differentiation, activation, proliferation, activity; or cytokine production or activity) in an individual to its presence or amount in persons known to suffer from, or known to be at risk of, the disease or condition (e.g. a neurodegenerative disease or disorder), or in persons known to be free of the disease (e.g. neurodegenerative disease or disorder such as Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease), and assigning an increased or decreased probability of having/ developing the disease or condition (e.g.

neurodegenerative disease or disorder such as Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease) to an individual based on the assay result(s). In some embodiments, determining whether a subject has or is at risk of having a disease or condition includes one or more of the following actions: collecting a sample from a subject, exposing the subject or sample to an antigen, antibody, antibody fragment, antibody derivative, multimer, protein, peptide or epitope, purifying the sample, measuring a characteristic of the sample, analysing the results of the

measurement; to be followed by assigning a probability of the subject having or developing the disease or condition. "Indicating" in reference to correlating a measured quantity with whether a patient has or is at risk of developing a disease or condition (e.g. neurodegenerative disease or disorder such as Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease) means that the correlation strongly implies or points toward the recited outcome. "Indicating", as described in the immediate preceding sentence, may also mean that a positive outcome of a test equates to a positive answer to the correlation.

[0066] "Nucleic acid" or "oligonucleotide" or "polynucleotide" or grammatical equivalents used herein means at least two nucleotides covalently linked together.

Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. A nucleic acid of the present invention will generally contain phosphodiester bonds, although in some cases, nucleic acid analogs are included that may have alternate backbones, comprising, e.g.,

phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphophoroamidite linkages (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press); and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose- phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.

[0067] A particular nucleic acid sequence also implicitly encompasses "splice variants." Similarly, a particular protein encoded by a nucleic acid implicitly

encompasses any protein encoded by a splice variant of that nucleic acid. "Splice variants," as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different

(alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition. An example of potassium channel splice variants is discussed in Leicher, et al., J. Biol. Chem. 273(52):35095-35101 (1998).

[0068] Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are near each other, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is

accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0069] The term "probe" or "primer", as used herein, is defined to be one or more nucleic acid fragments whose specific hybridization to a sample can be detected. A probe or primer can be of any length depending on the particular technique it will be used for. For example, PCR primers are generally between 10 and 40 nucleotides in length, while nucleic acid probes for, e.g., a Southern blot, can be more than a hundred nucleotides in length. The probe may be unlabelled or labelled as described below so that its binding to the target or sample can be detected. The probe can be produced from a source of nucleic acids from one or more particular (preselected) portions of a

chromosome, e.g., one or more clones, an isolated whole chromosome or chromosome fragment, or a collection of polymerase chain reaction (PCR) amplification products. The length and complexity of the nucleic acid fixed onto the target element is not critical to the invention. One of skill can adjust these factors to provide optimum hybridization and signal production for a given hybridization procedure, and to provide the required resolution among different genes or genomic locations.

[0070] The probe may also be isolated nucleic acids immobilized on a solid surface (e.g., nitrocellulose, glass, quartz, fused silica slides), as in an array. In some embodiments, the probe may be a member of an array of nucleic acids as described, for instance, in WO 96/17958. Techniques capable of producing high density arrays can also be used for this purpose (see, e.g., Fodor (1991) Science 767-773; Johnston (1998) Curr. Biol. 8: R171-R174; Schummer (1997) Biotechniques 23 : 1087-1092; Kern (1997) Biotechniques 23 : 120-124; U.S. Patent No. 5,143,854).

[0071] A "labelled nucleic acid probe or oligonucleotide" is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the probe may be detected by detecting the presence of the label bound to the probe. Alternatively, method using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., biotin, streptavidin.

[0072] The terms "identical" or "percent sequence identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site at ncbi.nlm.nih.gov/BLAST/ or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0073] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0074] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith &

Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FAST A, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

[0075] A preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information

(http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89: 10915 (1989)) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0076] The phrase "selectively (or specifically) hybridizes to" refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence with a higher affinity, e.g., under more stringent conditions, than to other nucleotide sequences (e.g., total cellular or library DNA or RNA).

[0077] The phrase "stringent hybridization conditions" refers to conditions under which a nucleic acid will hybridize to its target sequence, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes, "Overview of principles of hybridization and the strategy of nucleic acid assays" (1993). Generally, stringent hybridization conditions are selected to be about 5- lOoC lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength pH. The Tm is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at Tm, 50% of the probes are occupied at equilibrium). Stringent hybridization conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, preferably 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5x SSC, and 1% SDS, incubating at 42oC, or, 5x SSC, 1% SDS, incubating at 65oC, with wash in 0.2x SSC, and 0.1% SDS at 65oC. Exemplary "moderately stringent hybridization conditions" include a

hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37oC, and a wash in IX SSC at 45oC. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. Additional guidelines for determining hybridization parameters are provided in numerous reference, e.g., and Current Protocols in Molecular Biology, ed. Ausubel, et al., John Wiley & Sons.

[0078] Nucleic acids may be substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions.

[0079] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

[0080] The term "protein plaques and tangles" refers to clusters comprised of proteins or pieces of proteins. Protein plaques and tangles can comprise two or more different protein or pieces from two or more different proteins. In certain embodiments, proteins plaques and tangles comprise modified forms of proteins found in the central nervous system (e.g. one or more of the proteins listed in Table 1 or 2)

[0081] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, selenocysteine, pyrrolysine, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

[0082] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the njPAC-IUB

Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0083] As used herein "subsequence" refers to a portion of a protein or peptide that is that at least one amino acid less in length than the full-length protein or peptide.

[0084] As used herein "variant" and grammatical variations thereof, refers to a protein or peptide that deviates from a reference protein or peptide sequence. Modified and variant proteins or peptides may therefore have greater or less activity or function than a reference protein or peptide but at least retain partial activity or function of the reference protein or peptide. [0085] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of

conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence with respect to the expression product, but not with respect to actual probe sequences.

[0086] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid.

Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.

[0087] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).

[0088] As used herein a "modified" or "modification" also refers to a change to a protein or peptide that results in a deviation from a reference protein or peptide that can include for example Phosphorylation; De-phosphorylation; Oxidization; Reduction;

Citrullination; Glycatation (including but not limited to: prenylation, myristylation, palmitoylation; isoprenylation; farnesylation; geranylgeranylation; glpiation); Acylation; Alkylation; Amidation; Arginylation; Polyglutamylation; Polyglycylation;

Adenylylation; Sulfation; Carbamylation; Carbonylation; Glutathionylation;

Succynlation; Nitration; Nitrosylation; Di-sulfide bonding (Cysteine);

Transglutamination; Deamidation; Misfolding; Aggregation; Ubiquitination;

Sumoylation; Racemization, Single amino acid substitutions; Genetic frameshift mutations. The aforementioned modifications are not intended to be limiting by scope or category but rather an illustration of how proteins or peptides may be modified.

[0089] A "label" or a "detectable moiety" is a composition detectable by

spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0090] The term "recombinant" when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non- recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.

[0091] The term "heterologous" when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0092] "Antibody" refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad

immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.

Typically, the antigen-binding region of an antibody will be most critical in specificity and affinity of binding. In some embodiments, antibodies or fragments of antibodies may be derived from different organisms, including humans, mice, rats, hamsters, camels, etc. Antibodies of the invention may include antibodies that have been modified or mutated at one or more amino acid positions to improve or modulate a desired function of the antibody (e.g. glycosylation, expression, antigen recognition, effector functions, antigen binding, specificity, etc.).

[0093] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N- terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively. [0094] Antibodies exist, e.g., as intact immunoglobulins or as a number of well- characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments or derivatives either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature

348:552-554 (1990)).

[0095] In particular embodiments, the compositions and methods described herein comprise administering an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, (e.g. one or more of the proteins listed in Table 1 or 2) or protein plaques or tangles comprising the same. In particular embodiments, the method described herein comprises administering an antibody, antibody fragment or antibody derivative (e.g. Fab) that binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cell and/or one or more cytokines. In certain embodiments, the Fab binds a combination of proteins, immune cells and/or cytokines.

[0096] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Patent 4,946,778, U.S. Patent No. 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625, 126; 5,633,425; 5,661,016, Marks et al., Bio/Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13 :65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829,

Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in

Enzymology 121 :210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).

[0097] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U.S. Patent Nos. 4,816,567; 5,530, 101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87/02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321 :522; and Verhoyen et al. (1988) Science 239: 1534). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non- human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81 :6851-6855 (1984), Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239: 1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun, 28:489-498 (1991); Padlan, Molec. Immun, 31(3): 169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.

[0098] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. The preferred antibodies of, and for use according to the invention include humanized and/or chimeric monoclonal antibodies. [0099] In certain embodiments, the antibody binds a protein, including but not limited to a protein derived from a glial or neuronal cell. In particular embodiments, the antibody binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cells or one or more cytokines. In other embodiments, the antibody binds a combination of proteins, immune cells and/or cytokines.

[00100] In one embodiment, the antibody is conjugated to an "effector" moiety. The effector moiety can be any number of molecules, including labeling moieties such as radioactive labels or fluorescent labels, or can be a therapeutic moiety. In one aspect the antibody modulates the activity of a protein or immune cell. Such effector moieties include, but are not limited to, an anti-inflammatory drug, autoimmune disease drug, a toxin, a radioactive agent, a cytokine, a second antibody or an enzyme. Further, the invention provides an embodiment wherein the antibody of the invention is linked to an enzyme that converts a prodrug into a cytotoxic or immune response modulating agent.

[00101] The immunoconjugate can be used for targeting the effector moiety to an immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.). In certain embodiments, the immunoconjugate can be used to target immune cells involved in an innate immune response. In certain embodiments, the immunoconjugate can be used to target immune cells involved in an adaptive immune response. In certain embodiments, the immunoconjugate can be used to target immune cells involved in an immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the immunoconjugate can be used to target immune cells involved in an immune response that is specific to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00102] Additionally, recombinant proteins of the invention comprising the antigen-binding region of any of the monoclonal antibodies of the invention can be used to treat neurodegenerative diseases. In such a situation, the antigen-binding region of the recombinant protein is joined to at least a functionally active portion of a second protein having therapeutic activity.

[00103] [0001] Techniques for conjugating therapeutic agents to antibodies are well known (see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery"in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies '84: Biological And Clinical

Applications, Pinchera et al. (eds.), pp. 475-506 (1985); and Thorpe et al., "The

Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62: 119-58 (1982)).

[00104] In certain embodiments, the antibody binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cells or one or more cytokines. In other embodiments, the antibody binds a combination of proteins, peptides immune cells and/or cytokines.

[00105] [0002] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," when referring to a protein or peptide or modified protein, refers to a binding reaction that is determinative of the presence of the protein, peptide or modified protein, often in a heterogeneous population of proteins, peptides and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of

immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein or epitope. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific

immunoreactivity) .

[00106] The phrase "an immune response that is specific to" when referring to a protein or peptide or modified protein, refers to an immune response that is determinative of the presence of the protein, peptide or modified protein, often in a heterogeneous population of proteins, peptides and other biologies. Thus, the immune response detected is an immune response that is specific to that protein or peptide or modified protein, e.g. T cells or B cells that specifically recognize that protein or peptide or modified protein or have a detectably greater response to that specific protein or peptide or modified protein when compared to the response to other proteins or peptides.

[00107] A "protein level" refers to an amount (relative or absolute) of protein form (as distinguished from its precursor RNA form). A protein indicative of an immune response may include a full-length protein (e.g. the protein translated from the complete coding region of the gene, which may also include post-translational modifications), functional fragments of the full length protein (e.g. sub-domains of the full length protein that possess an activity or function in an assay), or protein fragments which may be any peptide or oligopeptide of the full length protein. In certain embodiments of the present invention, the method comprises measuring the protein level of a cytokine or other protein expressed by an immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.). For example, in certain embodiments, the method comprises measuring the level of mediators of T cell activity including for example cytokines, immune activators, chemokines, growth factors and TNF family members.

[00108] An "RNA level" refers to an amount (relative or absolute) of RNA present that may be translated to form a protein. The RNA may be a full-length RNA sufficient to form a full-length protein. The RNA may also be a fragment of the full length RNA thereby forming a fragment of the full-length protein. The fragment of the full length RNA may form a functional fragment of the protein.

[00109] As used herein, the term "pharmaceutically acceptable" is used synonymously with "physiologically acceptable" and "pharmacologically acceptable". A pharmaceutical composition will generally comprise agents for buffering and

preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.

[00110] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable carrier" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.

[00111] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[00112] In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[00113] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[00114] An "agent" as used herein refers to any molecule (e.g. antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer small chemical molecule, ligand mimetic, peptide, protein) that can be administered to a subject. In certain embodiments of the methods provided herein, the agent detects an immune response. In other embodiments of the methods provided herein, the agent characterizes an immune response, e.g. identifies the type of immune cell that is stimulated, activated, differentiated or proliferate in the immune response. In other embodiments of the methods provided herein, the agent modulates an immune response. An agent that modulates an immune response is a molecule (e.g. antibody, antibody fragment, antibody derivative (e.g Fab), nucleic acid, synthetic chemical, small chemical molecule, ligand mimetic, peptide, protein) that when administered to a subject modulates an immune response in the subject. In certain embodiments, the agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response. In some embodiments, the agent modulates stimulation, activation, differentiation, proliferation, number or activity of immune proteins or cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines etc.) In certain embodiments, the agent modulates an innate immune response. In certain embodiments, the agent modulates an adaptive immune response. In particular embodiments, the agent modulates an immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments, the agent modulates binding of an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments, the agent depletes B cells and/or T cells, including for example autoreactive B cell and T cells, and

autoreactive B cells and T cells specific for one or more of the proteins in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00115] In some embodiments, an agent is an agent (e.g. an antibody, antibody fragment, antibody derivative (e.g. Fab)) that binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the agent is an agent (e.g. an antibody or antibody derivative [e.g. Fab2 or Fab) that binds to a region or binding site of one of the proteins listed in Table 1 or 2, or a modification, subsequence, homologue, variant or derivative thereof, that is different from the region or binding site that autoantibodies generated against the protein, or modification, subsequence, homologue, variant or derivative thereof, in the subject bind. In some such embodiments, the agent may compete with autoantibodies for binding to the protein and may be selected or designed as an agent that modifies or inhibits pathogenic autoimmune responses. In other embodiments, the agent is a multimer, for example a multimer (e.g. a tetramer or dextramer) comprising a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00116] As used herein, "interaction", "interacting", "binding" or "bind" refers to a physical interaction at the molecular level or functional interaction between two or more of an agent, protein, peptide, molecule, immune cell, immune protein or nucleic acid. A functional interaction need not require physical binding. Accordingly, binding between two or more of an agent, protein, peptide, molecule, immune cell, immune protein or nucleic acid can be direct or indirect. A particular example of an indirect interaction is where one entity acts upon an intermediary molecule, which in turn acts upon the second referenced entity.

[00117] In some embodiments, the agent modulates or disrupts the interaction between an immune cell or immune protein and a physiological or natural ligand. As used herein, "immune protein" refers to a protein involved in an immune response including but not limited to proteins expressed by an immune cell (e.g. T cell, B cell, macrophage, monocyte, dendritic cell etc.) including but not limited to cytokines, integrins and tumor necrosis factor (T F) proteins. In some embodiments, the agent binds a physiological or natural ligand of the immune cell or immune protein. In some embodiments, the agent binds the complex an immune cell or immune protein bound to a ligand. In some embodiments, the agent disrupts the interaction between an immune cell or immune protein and one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the agent binds an immune cell or immune protein that interacts with one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the agent binds one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the agent binds the complex of an immune cell or immune protein bound to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00118] Thus in particular embodiments, the agent modulates the activity or expression of one or more type of immune cell or protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof. In some embodiments, the agent modulates the stimulation of T cells, activation of T cells, differentiation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof. In some embodiments, the agent modulates the stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof. In some embodiments, the agent modulates stimulation, differentiation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof). In some embodiments, the agent modulates production or activity of cytokines. In some embodiments, the agent modulates activity or expression of immune cells or proteins involved in an immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the agent modulates binding of autoantibodies to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, the agent modulates stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the agent modulates stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the agent modulates stimulation, differentiation activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies. In particular embodiments, the agent modulates stimulation, differentiation activation, proliferation, number or activity, or a combination thereof, of autoantibodies.

[00119] In some embodiments, the agent preferentially binds to an RNA that is translatable to a protein involved in an immune response (e.g. cytokine, TNF proteins, integrin etc.) compared to an RNA that is translatable to another nucleic acids. In some embodiments, the RNA is mRNA. In some embodiments, the agent is a protein, nucleic acid, ligand, ligand mimetic, small chemical molecule, antibody, antibody fragment, or antibody derivative (e.g. Fab). In some embodiments the agent binds a full length protein (e.g. the protein translated from the complete coding region of the gene, the complete RNA that is translatable to an full length immune protein, or complete coding DNA of the immune protein, which may also include post-translational modifications or post- transcriptional modifications). In some embodiments, the agent binds a fragment of the full length protein, RNA that is translatable to a fragment of the immune protein or DNA that is transcribable to a fragment of the immune protein or a functional fragment of the full length immune protein, RNA that is translatable to a functional fragment of the immune protein, or DNA that is transcribable to a functional fragment of the immune protein. In some embodiments the agent binds one or all splice variants of an immune protein.

[00120] In some embodiments, the agent is an antisense nucleic acid that is capable of hybridizing to an RNA that is translatable to an immune protein. The antisense nucleic acid is typically capable of decreasing the amount of immune protein that is translated in a cell.

[00121] An "RNAi molecule" is an siRNA, shRNA, miRNA, shmiRNA that is capable of inducing RNAi and hybridizing to an RNA that is translatable to an immune protein. The RNAi molecule is typically capable of decreasing the amount of immune protein that is translated in a cell.

[00122] A "ligand mimetic" is a synthetic chemical compound designed to mimic, in structure or in binding mode, a known ligand. For example, a ligand mimetic may bind the same amino acids or a subset of the same amino acids on an immune protein that a natural ligand of the immune protein binds during the physiological functioning of the immune protein. Ligand mimetics include biopolymers (e.g. proteins, nucleic acids, or sugars), lipids, chemical molecules with molecular weights less than five hundred (500) Daltons, one thousand (1000) Daltons, five thousand (5000) Daltons, less than ten thousand (10,000) Daltons, less than twenty five thousand (25,000) Daltons, less than fifty thousand (50,000) Daltons, less than seventy five thousand (75,000), less than one hundred thousand (100,000), or less than two hundred fifty thousand (250,000) Daltons. In some embodiments, the synthetic chemical compound is greater than two hundred fifty thousand (250,000) Daltons. In certain embodiments, the agent is less than five hundred (500) Daltons.

[00123] In some embodiments, a ligand mimetic is a small chemical molecule. A "small chemical molecule" is a molecule that has a molecular weight of less than two thousand (2000) Daltons. In some embodiments, a small chemical molecule is a molecule that has a molecular weight of less than one thousand (1000) Daltons. In other embodiments, a small chemical molecule is a molecule that has a molecular weight of less than five hundred (500) Daltons.

[00124] An agent may "target" a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell by preferentially binding to the protein, peptide, immune protein or immune cell, or RNA of a protein, peptide, immune protein or immune cell compared to its binding to other molecules of a similar form. An agent preferentially binds to a molecule, for example, when the binding to the targeted molecule is greater than the binding to other molecules of a similar form. In some embodiments, the preferential binding is 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5- fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8- fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, 6000-fold, 7000-fold, 8000-fold, 9000-fold, 10000 fold, 100,000-fold, 1,000,000-fold greater.

[00125] An agent may also "target" a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell by decreasing or increasing the amount of a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell in a cell or organism relative to the absence of the agent. A person having ordinary skill in the art, using the guidance provided herein, may easily determine whether an agent decreases or increases the amount of a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell a cell or organism.

[00126] Methods of determining whether a subject has or is at risk of developing a neurodegenerative disease

[00127] Provided herein are methods of determining whether a subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease. The present inventors have found that neurodegenerative diseases are associated with a modulated immune response in the subject relative to individuals who do not have or are not at risk of developing a neurodegenerative disease or disorder. The methods of the present invention can also determine the severity of a neurodegenerative disease or disorder in a subject.

[00128] In some embodiments, the modulated activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increased activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increased expression of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, is associated with a

neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increased stimulation, differentiation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same) is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the increase in production or activity of cytokines is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, increased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In particular embodiments, increased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder.

[00129] In some embodiments, the decreased activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decreased expression of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decreased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, is associated with a

neurodegenerative disease or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decreased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decreased

stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same) is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decreased production or activity of cytokines is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In some embodiments, the decrease in activity or expression of immune cells or immune proteins results from a decrease in an immune response to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same). In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, a decreased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder. In particular embodiments, a decreased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with a neurodegenerative disease or disorder or a risk of developing a neurodegenerative disease or disorder.

[00130] In some embodiments, the increased expression or activity of a first immune cell or immune protein and the decreased expression or activity of a second immune cell or immune protein is associated with a neurodegenerative disease or a risk of developing a neurodegenerative disease or disorder.

[00131] In other embodiments, a modulation (e.g. increase or decrease) in production or activity of mediators of immune cell activity (e.g. cytokines, immune activators, chemokines, growth factors and TNF family members, including for example is AREG, Granzyme, Histamine, IFNa/b, IFNg, IL12, IL15, IL16, IL17a-f, ILlb, 112, IL21, IL22, IL23, IL25, IL27, GM-CSF, IL33, IL4, IL5, IL6, IL7, IL8, IL9, LFA-1, LIF, lymphotoxin, Mac-1, MCP-1, MlPla, Perforin, TGF-B, TNF a, VLA-4, CCL1, CCL11, CLL17, CCL1, CCL20, CCL22, CCL3, CCL4, CCL5, CXCL10, CXCL13, CXCL8, RANTES, CXCL12, G-CSF, M-CSF, VEGF, PDGF, 4-1BB, APRIL, BAFF, CD27, CD30, CD30L, CD70, DR3, DR4, DR5, FAS, FASL, GITR, HVEM, LIGHT, LTB, OX40, Ox40L, TACI, TRAIL, TWEAK, IL11, IL14 or IL10.) is associated with a neurodegenerative disease or disorder. In some embodiments, a modulation in the production of autoantibodies (e.g. autoantibodies to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof) is associated with a neurodegenerative disease or disorder. In other embodiments, a modulation in the amount of autoreactive immune cells (e.g. T cells or B cells) including for example immune cells that are reactive to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof) is associated with a neurodegenerative disease or disorder. In some embodiments, a modulation in activity or expression of immune cells or immune proteins results from an immune response to a protein, including but not limited to a protein or peptide derived from a glial or neuronal cell, one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00132] Therefore, in certain embodiments, there is provided a method of determining whether a subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease comprising determining whether the subject has a modulated immune response wherein a modulated immune response indicates that the subject has, is at risk of having, or is in need of treatment for a neurodegenerative disease. In certain embodiments, the method comprises one or more reagents that can detect biomarkers of particular interest.

[00133] Non-limiting examples of conditions, diseases or disorder that may be associated with a differential expression or activity of immune cells, antibodies or proteins as detected in the methods of the present invention include as Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease.

[00134] The method of determining whether a subject has or is at risk of developing a neurodegenerative disease or disorder may also be a method of diagnosing a subject (e.g. a patient) or providing the subject with a prognosis. In some embodiments, the method includes determining whether a subject has or is at risk of developing a neurodegenerative disease. The method includes determining whether a subject expresses a modulated immune response relative to a standard control. The presence of a modulated immune response indicates the subject has or is at risk of developing a neurodegenerative disease.

[00135] In some embodiments, the methods of the present invention includes determining whether the subject has a modulated immune response to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the method includes determining whether the subject has a modulated T cell, B cell or cytokine response. In particular embodiments, the method includes determining whether the subject has one or more of stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, increased number of T cells, increased activity of T cells, stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, increased number of B cells, increased activity of B cells, increased production or activity of autoantibodies or increased production or activity of mediators of T cell activity.

[00136] In some embodiments, the methods of the present invention include detecting B cells generating autoantibodies. In some embodiments, the methods described herein the method comprises detecting B cells generating autoantibodies to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00137] In some embodiments, the methods of the present invention include detecting antibodies, including autoantibodies present in a subject. In some embodiments, the methods of the present invention include detecting autoantibodies to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00138] In certain embodiments, the methods of the present invention include detecting a modulated innate immune response. In other embodiments, the methods of the present invention include detecting an adaptive immune response. In certain

embodiments, the methods of the present invention include detecting an immune response (e.g. adaptive immune response) specific to a protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00139] In certain embodiments, the methods described herein comprise detection of an immune complex (IC). In particular embodiments, the immune complex detected comprises a protein or peptide bound to an autoantibody. In certain embodiments, the IC comprises complement proteins bound to one or both of the protein or peptide or the autoantibody in the IC. In particular embodiments, the protein in the immune complex is a protein listed in Table 1 or 2 or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments, the peptide in the IC is a peptide listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the autoantibody in the IC is an antibody against one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00140] In certain embodiments, the methods of the present invention comprise detecting two or more different ICs each comprising different proteins listed in Table 1 or 2, or peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00141] In a preferred embodiment, the method of diagnosing a neurodegenerative disease is disorder is implemented in a diagnostic kit that measures an immune complex. The specific immune complex comprises at least one antibody and at least one antigen (e.g. protein or peptide). Thus, in particular embodiments, the methods and kits of the present invention include one or more reagents to bind the IC. In different embodiments, the present invention includes a first reagent to bind the antigen and a second reagent to bind the antibody wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of an IC. In other embodiments, the present invention contains a first reagent to bind the antigen and a second reagent to bind a complement protein wherein the binding of the second reagent to the complement protein is measured to determine the presence or amount of an IC. In particular embodiments the antigen is a protein, including for example a protein listed in Table 1 or 2, or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments the antigen comprises a peptide, including for example a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments the antibody is an autoantibody, including for example an autoantibody that binds a protein listed in Table 1 or 2, a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00142] In an embodiment, the method comprises one or more reagents that can detect biomarkers of particular interest. In an embodiment the method uses a reagent for detecting an IC comprising one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In further embodiments, the method further comprises a reagent for detecting one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, or an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the reagent for detecting the IC is a derivative of a protein, antibody or Fab fragment that binds the IC.

[00143] In certain embodiments, methods and kits of the present invention comprise a Fab that binds an IC comprising one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In other embodiments, the method described herein further comprises a Fab that binds one or more of the proteins listed in Table 1 or 2 or one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cell, one or more autoantibodies and/or one or more cytokines. In certain embodiments, the Fab binds a combination of proteins, peptides immune cells and/or cytokines.

[00144] In particular embodiments, the IC is detected using a reagent that does not bind to an immunogenic epitope of a protein or peptide, for example a protein listed in Table 1 or 2, a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, use of a reagent that bindsto sites on a protein of an immune complex other than immunogenic epitopes of that protein generates a significantly more accurate measurement of the presence of an immune complex associated with a neurodegenerative disease or disorder. Without being limited to any particular theory, a reagent that does not bind to an immunogenic epitope of the protein or peptide may provide more effective binding to a protein listed in Table 1 or 2 or a peptide listed in any of Tables 3 to 102 as it does not bind the protein or peptide at the same site as an autoantibody and therefore does not need to compete with autoantibodies for binding of the protein or peptide.

[00145] In particular embodiments of the present invention, the concentration of the IC is analyzed against a known concentration baseline for the IC and subsequent measurements of the IC in subjects with a neurodegenerative disease or disorder.

[00146] In particular embodiments, the present invention comprises detecting an IC in combination with one or more of a protein cytokine, auto-antibody, T cell, B cell, protein-specific T cell response or protein-specific B cell response. In more particular embodiments, the concentrations of the biomarkers are analyzed against a known concentration baseline for each type of biomarker. In further embodiments, the concentrations of each biomarker are analyzed in cross-references to each other and over multiple time points either prior to or post the onset of a neurodegenerative disease or disorder or the start of a treatment for neurodegenerative disease or disorder. [00147] In different embodiments, the present method comprises detecting or measuring one or more IC comprising one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, alone or in combination with other biomarkers selected from the group consisting of one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, one or more cytokine, one or more

autoantibody that binds one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell responding to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell responding to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell response to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell response to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof.

[00148] In different embodiments, the present method comprises detecting one or more IC comprising one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof in combination with biomarkers selected from two or more, three or more, four or more, five or more, six or more or seven of the group consisting of one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, one or more cytokine, one or more autoantibody that binds one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell responding to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell responding to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell response to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell response to one or more protein listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof.

[00149] In an embodiment, concentrations of one or more ICs alone or in combination with one or more proteins, one or more cytokines, one or more autoantibodies, one or more T cells, one or more B cells and one or more B cell and/or T cell responses can be measured prior to and post the onset of a neurodegenerative disease or start of treatment for neurodegenerative disease. In an embodiment, groups of thresholds can be determined for the concentration of each biomarker at specific points in time. In a preferred embodiment the thresholds are correlated to a probability of whether immune- mediated damage or the onset of a neurodegenerative disease or disorder can occur. In a preferred embodiment the threshold data groups are compared with a subject's immune response over the same time periods. In specific embodiments, the up regulation of the auto-specific immune response or the waning of the immune response can be key indicators of the severity and pathogenesis of a neurodegenerative disease.

[00150] In certain embodiments, the present methods comprise determining or developing an immune profile of a subject by characterization of immune responses that have occurred or are likely to occur in a subject. In particular embodiments, the methods may include detecting proteins or peptides that have elicited an immune response in a subject or that are likely to elicit an immune response in a subject, for example determining which proteins or peptides of the central nervous system, (such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof) have elicited an immune response in a subject or are likely to elicit an immune response in a subject. The methods may include detecting biomarkers, including for example B cells, T cells, ICs, antibodies or cytokines. In particular embodiments, the methods including detecting biomarkers for one or more proteins or peptides of the central nervous system, such as B cells, T cells, ICs, or antibodies that are reactive or that bind to a particular protein of interest. In certain embodiments, the methods of the present invention may include obtaining a biological sample from a subject, exposing the sample to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, and detecting whether there are autoantibodies in the biological sample that bind to the protein or whether there are autoreactive T cells to the protein or peptide in the biological sample. Using such methods, one of skill in the art is able to determine a profile of which proteins or peptides have elicited an immune response in a subject or are likely to elicit an immune response in a subject and what kind of immune response has been elicited, e.g. B cell, T cell, antibody or cytokines. This information can inform diagnosis of diseases and disorders as well as identify what treatment options are appropriate for a subject or whether a particular treatment is effective.

[00151] A modulated RNA level or protein level associated with an immune response, modulated immune response level or other measured quantity relative to a control standard is a measured amount (e.g. of the RNA level, protein level, etc.) that differs from the measured or calculated amount of the same quantity in the standard control. In some embodiments, the measured quantity is greater than or elevated above or increased over the standard control. In further embodiments, the measured quantity is greater by or elevated above or increased over the standard control by at least 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. In some embodiments, the measured quantity is less than or decreased compared to the standard control. In further embodiments, the measured quantity is less than or decreased as compared to the standard control by at least 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The modulated level or amount of a measured quantity (e.g. immune response to one or more of the proteins listed in Table 1 or 2, or a subsequence, homologue, variant or derivative thereof) can be also be expressed as a "-fold" increase or decrease. For example, a measurable can be at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 5-fold, or larger-fold greater (e.g. elevated over) or less than a standard control.

[00152] A subject who is "at risk of developing" a condition or disease has greater chance to having the condition or disease than a person who is not at risk of developing the condition or disease. In some embodiments, a standard control is derived from the person who is not at risk of developing the condition or disease (i.e. standard control subject).

The amounts or levels of protein or RNA or immune cells or level of immune response may be measured in known assays or tests to determine if a subject is at risk of developing a condition or disease (e.g. neurodegenerative disease or disorder). In some embodiments, the person at risk of developing the condition or disease has at least a 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, or at least a 100% greater likelihood of having the disease at some future time relative to a standard control. In some embodiments that future time is one or more weeks, one or more months, or one or more years from the time at which the risk is assessed. In some embodiments, the subject at risk of developing the condition or disease is or is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 5-fold, 10-fold, 20-fold more likely to develop the condition or disease at some time in the future. In some embodiments, the standard control is a threshold level of a measurable quantity established by previous testing. The person at risk of developing the condition or disease may be a person that has the measurable quantity (e.g. immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof) in excess of or below the established threshold, depending on the measurable quantity. The threshold in the previous embodiment may be established by determining the differences between subjects who do not have the condition or disease (e.g. standard control) and subjects who have the condition disease, and assigning a threshold that separates one group from the other group in terms of one or more measurable quantities. [00153] In particular embodiments of the present invention the biomarker is prepared for detection and measurement using methods of detection known in the art. Known methods of detecting immune response include but are not limited to competitive and non-competitive formats, enzyme linked immunosorption assays (ELISA), microspot assays, Western blots, gel filtration and chromatography, immunochromatography, immunohistochemistry, flow cytometry or fluorescence activated cell sorting (FACS), microarrays, ELISPOT. In certain embodiments, detection or measurement of IC is done using antibodies, Fabs, protein or peptides that bind the protein contained in the IC and antibodies, Fabs, proteins or peptides that bind the autoantibody contained in the IC. In further embodiments, detection or measurement of IC is done using antibodies, Fabs, protein or peptides that bind one or more complement protein bound to one or both of the protein or autoantibody in the IC. In certain embodiments, detection or measurement of proteins and peptides can be done using antibodies, Fabs, proteins, peptides or ligand mimetics that bind the protein or peptide. In certain embodiments, detection or measurement of cytokines can be done using antibodies or Fabs that bind the cytokine. In certain embodiments, detection or measurement of autoantibodies is done using a protein or peptide that binds the autoantibody, such as a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof.

[00154] In some embodiments, the method of determining includes isolating a biological sample from the subject including but not limited to forming isolated immune cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells).

[00155] The terms "isolated" "purified" or "biologically pure" refer to material that is substantially or essentially free from components which normally accompany it as found in its native state. Purity and homogeneity of biological molecules (e.g. nucleic acids or proteins) are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. The term "purified" denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, optionally at least 95% pure, and optionally at least 99% pure. As an example, an isolated cell or isolated sample cells are a single cell type that is substantially free of many of the components which normally accompany the cells when they are in their native state or when they are initially removed from their native state. In some embodiments, an isolated cell sample retains those components from its natural state that are required to maintain the cell in a desired state. In some embodiments, an isolated (e.g. purified, separated) cell or isolated cells, are cells that are substantially the only cell type in a sample. A purified cell sample may contain at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of one type of cell. An isolated cell sample may be obtained through the use of a cell marker or a combination of cell markers, either of which is unique to one cell type in an unpurified cell sample. In some embodiments, the cells are isolated through the use of a cell sorter. In some

embodiments, antibodies against cell proteins are used to isolate cells.

[00156] The isolated cells may be of any appropriate type. In some embodiments, the isolated cells are immune cells, including but not limited to T cells, B cells, macrophages, monocytes and dendritic cells. In some embodiments, the biological sample is whole blood, plasma, serum, urine, sputum or saliva.

[00157] Immune cells include neutrophils, eosinophils, basophils, lymphocytes, B- cells, T-cells, Natural Killer cells (NK-cells), monocytes, macrophages, dendritic cells, or any cells derived from these cells.

[00158] Methods for detecting and identifying nucleic acids, proteins, cells and interactions between such molecules involve conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature (see, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition 1989, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Animal Cell Culture, R. I. Freshney, ed., 1986).

[00159] Nucleic acids of interest may also be amplified using a variety of known amplification techniques. For instance, polymerase chain reaction (PCR) technology may be used to amplify target sequences directly from DNA, RNA, or cDNA. In some embodiments, a stretch of nucleic acids is amplified using primers on either side of a targeted genetic variation, and the amplification product is then sequenced to detect the targeted genetic variation (using, e.g., Sanger sequencing, Pyrosequencing, Next gen sequencing technologies). For example, the primers can be designed to hybridize to either side of the upstream regulatory region of a protein expressed during an immune response, and the intervening sequence determined to detect a SNP in the promoter region. In some embodiments, one of the primers can be designed to hybridize to the targeted genetic variant.

[00160] Amplification techniques can also be useful for cloning nucleic acid sequences, to make nucleic acids to use as probes for detecting the presence of a target nucleic acid in samples, for nucleic acid sequencing, for control samples, or for other purposes. Probes and primers are also readily available from commercial sources, e.g., from Invitrogen, Clonetech, etc.

[00161] Expression of a given gene, e.g., a gene expressed by an immune cell, or another disease marker, or standard (control), is typically detected by detecting the amount of RNA (e.g., mRNA) or protein. Sample levels can be compared to a standard control level.

[00162] Methods for detecting RNA are largely cumulative with the nucleic acid detection assays described above. RNA to be detected can include mRNA or pRNA (promoter-associated RNA, see, e.g., Schmitz et al. (2010) Genes Dev. 24:2264-69). In some embodiments, a reverse transcriptase reaction is carried out and the targeted sequence is then amplified using standard PCR. Quantitative PCR (qPCR) or real time PCR (RT-PCR) is useful for determining relative expression levels, when compared to a control. Quantitative PCR techniques and platforms are known in the art, and commercially available (see, e.g., the qPCR Symposium website, available at

qpcrsymposium.com). Nucleic acid arrays are also useful for detecting nucleic acid expression. Customizable arrays are available from, e.g., Affimatrix. [00163] Protein levels can be detected using antibodies, antibody derivatives or antibody fragments specific for that protein, natural ligands, small molecules, aptamers, etc.

[00164] Multimers, including for example tetramers, can be used in the present methods to detect immune cells, for example T cells. In certain embodiments, the present methods comprise multimers comprising one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the present methods comprise use of the multimers to detect or measure the amount of immune cells that are specific for a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In other particular embodiment, the present methods comprise use of a multimer to characterize immune cells, for example to identify the type of immune cell that is stimulated, activated, differentiated or proliferated in a immune response (e.g. memory immune cell, naive immune cell, effector immune cell).

[00165] Antibody based techniques are known in the art, and described, e.g., in Harlow & Lane (1988) Antibodies: A Laboratory Manual and Harlow (1998) Using Antibodies: A Laboratory Manual; Wild, The Immunoassay Handbook, 3d edition (2005) and Law, Immunoassay: A Practical Guide (1996). The assay can be directed to detection of a molecular target (e.g., protein or antigen), or a cell, tissue, biological sample, liquid sample or surface suspected of carrying an antibody or antibody target.

[00166] Immune response, including the stimulation, differentiation, activation, proliferation of immune cells and the number and/or the number and activity of immune cells can be detected using assays known in the art. A non-exhaustive list of

immunoassays includes: competitive and non-competitive formats, enzyme linked immunosorption assays (ELISA), microspot assays, Western blots, gel filtration and chromatography, immunochromatography, immunohistochemistry, flow cytometry or fluorescence activated cell sorting (FACS), microarrays, ELISPOT. Such techniques can also be used in situ, ex vivo, or in vivo, e.g., for diagnostic imaging.

[00167] Aptamers are nucleic acids that are designed to bind to a wide variety of targets in a non-Watson Crick manner. An aptamer can thus be used to detect or otherwise target nearly any molecule of interest, including an inflammatory or immune response associated protein. Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Patent Nos. 5,582,981, 5,595,877 and 5,637,459. Aptamers are typically at least 5 nucleotides, 10, 20, 30 or 40 nucleotides in length, and can be composed of modified nucleic acids to improve stability. Flanking sequences can be added for structural stability, e.g., to form 3-dimensional structures in the aptamer.

[00168] In certain embodiments, a diagnostic method of the present invention may include, but is not limited to, alone or in combination, analysis of individual protein, mPvNA levels, and/or immune cell levels or activity.

[00169] The above methods of detection can be applied to additional markers of immune response. That is, the expression level or activity of a protein or immune cell that is a marker for modulated immune response can be determined, and compared to a standard control marker. The examination of additional proteins or immune cells that are markers for a modulated immune response can be used to confirm a diagnosis of neurodegenerative disease, monitor condition or disease progression, or determine the efficacy of a course of treatment in a subject.

[00170] In some embodiments, the presence of a modulated (e.g. elevated) RNA level, protein level protein, immune cell level or immune response level indicates the subject has a neurodegenerative disease or disorder. In some embodiments, the presence of the modulated RNA level, protein level protein, immune cell level or immune response level indicates the subject is at risk of developing a neurodegenerative disease or disorder.

[00171] In other embodiments, a method of the present invention is used to determine the efficacy of a therapeutic method or conventional treatment method. In an embodiment the invention is used with conventional diagnostic and treatment methods as a companion diagnostic tool.

[00172] Thus, in certain embodiments, the methods of the present invention are used to determine the efficacy of a treatment for a neurodegenerative disease or disorder in a subject. In such methods a biological sample is obtained from the subject following administration of the treatment and an immune response in the subject is measured. This is compared with the immune response in a control biological sample and a reduced immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the

neurodegenerative disease. In certain embodiments, the control biological sample is a biological sample taken from the subject prior to treatment. In particular embodiments, the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell and cytokine response.

[00173] In other embodiments the invention is used stratify patient population with respect to treatment approaches. For example, if an immune response to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is modulated and then diagnosed using the present invention, then this may indicate that certain treatments for neurodegenerative disease should be administered. In particular embodiments the diagnostic kit and its methods are implemented as screening tools for subjects who are suspected to have a neurodegenerative disease or disorder, are at risk of developing a neurodegenerative disease or disorder or would benefit from the knowledge of profiling. [00174] In certain embodiments, there is provided a method of determining whether a subject has, is at risk of having, or is in need of treatment for a

neurodegenerative disease or disorder comprising administering to the subject an agent that can detect a modulated immune response in the subject. In such embodiments, the subject may be administered a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject is detected. Detection of such binding indicates that there is an immune response to the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject and therefore that the subject has, is at risk of having, or is in need of treatment of a neurodegenerative response.

[00175] In other embodiments, the method comprises administering to the subject an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject. Detection of such binding indicate that there is a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof determines that the subject has, is at risk of having, or is in need of treatment of a neurodegenerative disease or disorder.

[00176] In still another embodiment, the method comprises administering to the subject a multimer comprising a peptide listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof. Detection of binding of such a multimer to immune cells (e.g. T cells) in the subject determines that the subject has, is at risk of having, or is in need of treatment of a neurodegenerative disease or disorder. In certain embodiments, the multimer is a tetramer or a dextramer. In particular embodiments, the multimer is used to detect the presence of immune cells responsive to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00177] In still other embodiments, there are provided methods for determining the efficacy of a treatment for a neurodegenerative disease or disorder in a subject comprising administering to the subject an agent that can detect a modulation in the immune response in the subject after the treatment from the immune response in the subject prior to treatment. The method may comprise administering to the subject after treatment a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof. In certain embodiments, the method comprises detecting binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein a decrease in the amount of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject when compared to the amount of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease or disorder.

[00178] In other embodiments, the present methods for determining treatment efficacy comprise administering to the subject after treatment an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject, wherein a decrease in the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject when compared to the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease or disorder.

[00179] In still other embodiments, the present methods for determining treatment efficacy comprise administering to the subject after treatment a multimer comprising a peptide listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof wherein a decrease in the amount of T cells that bind the multimer in the subject after treatment when compared to the amount of T cells that bind the multimer in the subject prior to treatment indicates that the treatment is effective in treating the neurodegenerative disease.

[00180] In different embodiments, the methods for determining efficacy of treatment comprise determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, antibody, immune cell mediator and cytokine response.

[00181] The methods of the present invention may also be used to stratify patient populations for treatment or determine an appropriate treatment for a subject to be treated for a neurodegenerative disease or disorder. Such methods comprise administering to the subject an agent that can detect a modulated immune response in the subject. In particular embodiments, such method comprises administering: (a) a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein detection of binding of the modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof to an antibody in the subject determines that the subject should be treated by modulating the immune response to the modified form of the one or more the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof; (b) an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof in the subject wherein detection of binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof determines that the subject should be treated by modulating the immune response to the modified form of the one or more the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof; or (c) a multimer comprising a peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof, and detecting binding of the multimer to a T cell in the subject, wherein detection of binding of the multimer to a T cell in the subject determines that the subject should be treated by modulating the immune response to the peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof, or a protein comprising the peptide listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof.

[00182] In the present methods of diagnosis comprising administering to the subject agents that detect an immune response, binding of the agent (e.g. modified protein or peptide, including for example a modified form of the one or more the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof; antibody or multimer) to an antibody, protein, peptide, modified protein, modified peptide or immune cell in the subject can be detected by various means known in the art including fluorescence, magnetic resonance imaging etc.

[00183] In other embodiments, the method of determining comprises administering to a subject or exposing a subject or tissue from the subject to an antigen, epitope or protein, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, and determining if there is an immune response. In particular examples, the method includes administering an antigen, protein, or epitope, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, subcutaneously or intradermally, and detecting whether there is an immune reaction (e.g. swelling or redness of the skin).

[00184] In particular embodiments, detecting the risk of the subject developing a neurodegenerative is determined by an initial detection of a biomarker (e.g. T cell, B cell, protein, antibody, IC, cytokine) indicating an onset of an adaptive immune response, which increases risk of development of a neurodegenerative disease In other

embodiments, the concentration of the biomarker can indicate the level of risk

neurodegenerative disease development. In particular embodiments, an analysis of the concentration levels of the biomarker on initial detection can indicate the level of risk for neurodegenerative disease. In other embodiments, initial detection of biomarkers may identify a subject for treatment of a neurodegenerative disease.

[00185] In certain embodiments of the present methods, measurements are taken at a single time point, for example after onset of a neurodegenerative disease or disorder. In other embodiments, measurements are taken at multiple time points to detect the severity of a neurodegenerative disease or disorder over time. In a preferred embodiment, the methods include measuring the concentration of specific biomarkers (e.g. T cell, B cell, protein, antibody, IC, cytokine) over multiple points in time. In one embodiment, initial measurements of specific biomarkers are taken at a point in time where it is known that a subject has not developed a neurodegenerative disease or disorder. In another

embodiment, initial measurement of specific biomarker are take at a point in time before a subject has an increased risk of development of neurodegenerative disease or disorder. In an embodiment these initial measurements act as a baseline or control to subsequent measurements where it is known that a subject has started to develop a neurodegenerative disease or disorder. In another embodiment these initial measurements act as a baseline or control to subsequent measurements after a subject has developed a neurodegenerative disease or disorder or has an increase risk of development of a neurodegenerative disease or disorder.

[00186] In other embodiments, the methods include measuring the concentration of specific biomarkers (e.g. T cell, B cell, protein, antibody, IC, cytokine) over multiple points in time. In one embodiment, initial measurements of specific biomarkers are taken at a point in time where it is known that the subject has developed a neurodegenerative disease. In an embodiment, these initial measurements act as a baseline or control to subsequent measurements, which are taken following further development of the neurodegenerative disease or an associated symptom.

[00187] In a preferred embodiment, the methods include measuring the

concentration of specific biomarkers over multiple time point in time including for example before and after administration to the subject of a treatment for a

neurodegenerative disease. In one embodiment, initial measurements of specific biomarkers are taken at a point in time before administration of the treatment. In an embodiment, these initial measurements act as a baseline or control to subsequent measurements, which are taken following treatment of the subject. In an embodiment, the subsequent measurements are taken post treatment. In a further embodiment, subsequent measurements are taken following subsequent administration of the treatment. [00188] In certain embodiments, the measurements taken over multiple points can provide a profile for the immune response in a subject, which can reveal trends in the immune response in the subject. This information can provide insight with regard to the severity of a neurodegenerative disease or the efficacy of a treatment that is being administered to the subject to treat a neurodegenerative disease. In other embodiments, this information can be used to determine if or when a subject should begin treatment for a neurodegenerative disease.

[00189] Without being limited to any particular theory, measuring the biomarkers at multiple time points provides more accurate information as to whether the biomarkers are increasing and the rate at which the biomarkers increase and decrease over time in the subject following development of a neurodegenerative disease or treatment for a neurodegenerative disease. This information may allow for a more accurate

determination of whether a subject has a neurodegenerative disease and the level of severity of the neurodegenerative disease.

[00190] In other iterations, and without being limited to any particular theory, measuring biomarkers over multiple time points allows determination of trends of the presence and amount of biomarkers in a subject. This information can be used to determine risk for that subject in developing neurodegenerative disease or disorder and to make decisions regarding treatment. For example, a trend of a continuous increase in amount of biomarkers detected may indicate that the subject is at an increased risk of developing a severe neurodegenerative disease or disorder. Alternatively, in a subject receiving treatment for a neurodegenerative disease or disorder, a trend of decrease in amount to biomarkers detected following each subsequent treatment, may indicate that the treatment is effective.

[00191] The present invention provides kits for detection of immune response markers (e.g. biomarkers) in a subject. The kit can be a kit for diagnosing or prognosing a neurodegenerative disease or disorder, for determining the severity of a

neurodegenerative disease or disorder, for monitoring the progression of the

neurodegenerative disease or disorder, for determining the efficacy of treatment or for stratifying patients for a particular treatment.

[00192] In some embodiments, the kit includes components for assessing immune response, including but not limited to components for detecting the expression level or activity of a RNA, protein or immune cells, e.g. a nucleic acid, protein, peptide, multimer, antibody, antibody derivative, antibody fragment (e.g. Fab)or other agent capable of detecting the number or activity of immune cells or level of proteins or antibodies expressed by immune cells. These agents may be optionally labeled. One of skill will appreciate that an immune response can be determined by measuring immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.) stimulation, differentiation, activation, proliferation, number and activity. The kit can further include assay containers (tubes), buffers, or enzymes necessary for carrying out the detection assay. Other components in a kit can include, DNA sequencing assay components, Taqman ® genotyping assay components, Meta Analysis, one or more detection system(s), one or more control samples or a combination thereof.

[00193] In certain embodiments, the kits of the present invention include an agent that can detect the presence of a B cell generating autoantibodies. In particular embodiments, the kit includes an agent that can detect B cells generating autoantibodies wherein the autoantibodies are against a protein, including but not limited a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the kit includes components to examine more than one immune response marker. For example, the kit can include marker detection agents, such as marker specific primers or probes attached to an addressable array. Exemplary markers include T cells, B cells, autoantibodies, mediators of T cells activity (e.g. cytokines), or immune response associated cells or proteins. In some embodiments, the genetic sequence of the markers is detected instead of the expression level of the markers. In other embodiments, the stimulation, activation, proliferation, or activity of markers is detected. [00194] In particular embodiments, the kit includes one or more protein or peptide, including but not limited to a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, to detect the level of immune cell stimulation, proliferation, differentiation, number or activity in the biological sample or patient. In other embodiments, the kit includes a multimer (e.g. a tetramer or dextramer) comprising one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00195] In certain embodiments, the kit comprises an antibody, antibody derivative or Fab that can bind one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. The kit may include one or more antibodies or Fabs (e.g. a panel of antibodies or Fabs) each of which binds different proteins listed in Table 1 or 2 or peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00196] In certain embodiments, the kit also includes means to measure B cell and/or T cell stimulation, proliferation, differentiation, number or activity. In particular embodiments, the kit includes means to measure autoreactive immune cells (e.g. B cell and T cells) including for example immune cells reactive to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In other

embodiments, the kit includes means to measure autoantibodies to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the kit includes antibodies to detect the presence or amount of mediators immune cell activity (e.g. T cell activity) or cytokines in the biological sample.

[00197] In an embodiment, the diagnostic kit comprises one or more reagents that can detect biomarkers of particular interest, which result from or are associated with neurodegenerative disease. These reagents are specifically selected for the desired biomarker indication. The biomarkers may be located on an exterior surface of a component of a biological sample or are extracellular. The biomarkers comprise unique configurations and binding mechanisms allowing for a directed selection through specific corresponding reagents.

[00198] Thus, in an embodiment, the diagnostic kit has one or more reagents wherein the one or more reagents detect the presence of a biomarker in the biological sample. These reagents are configured to detect the quantity of the biomarker in a biological sample. The biological samples can be taken at one point in time, or at one point in time then subsequent times.

[00199] In particular embodiments, the diagnostic kit has one or more reagents to bind the IC. In different embodiments, the diagnostic kit contains a first reagent to bind the protein or peptide in the IC and a second reagent to bind the antibody of the IC that is binding the protein or peptide wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of an IC. In further embodiments, the diagnostic kit contains a reagent to bind one or more complement proteins bound to one or both of the protein, peptide or autoantibody in the IC.

[00200] In an embodiment, the diagnostic kit has at least one reagent for detecting an IC comprising one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof. In particular embodiments, the diagnostic kit further comprises a least one reagent for detecting one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102,or a modification, subsequence, homologue, variant or derivative thereof or an autoantibody to one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00201] In different embodiments, the diagnostic kit has at least one reagent for detecting one or more IC comprising one or more of one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof. In further embodiments, the diagnostic kit further comprises a least one reagent for detecting one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof or an autoantibody to one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof.

[00202] In an embodiment, a reagent is configured to not target specific regions of the biomarker, for example known epitopes of the biomarker. These specific regions are known to exist and the reagent will selectively avoid them to target desired regions existing on the biomarker (e.g. protein, peptide or antigen).

[00203] In different embodiments, the diagnostic kit has reagents for the detection of the biomarkers of interest individually or in combination. In different embodiments, the diagnostic kit has reagents for detecting an IC and protein; IC and cytokine; IC and autoantibody; IC, protein and cytokine; IC, protein and autoantibody; or IC, cytokine and autoantibody. In an embodiment, the reagent for detecting the IC is a protein, antibody or Fab that binds the IC. In an embodiment, the reagent for detecting a cytokine is an antibody that binds the cytokine. In an alternative embodiment, the reagent for detecting an autoantibody is a protein or peptide that binds the autoantibody. In an alternative embodiment, the reagent for detecting the protein is a protein, antibody or Fab that binds the protein. [00204] The kit may also include at least one vial, test tube, flask, bottle, syringe or other container means, into which the testing agent can be suitably reacted or aliquoted. Kits can also include components for comparing results such as a suitable control sample, for example a positive and/or negative control. The kit can also include a collection device for collecting and/ or holding the sample from the subject. The collection device can include a sterile swab or needle (for collecting bodily fluids), and/or a sterile tube (e.g., for holding the swab or a bodily fluid sample).

[00205] Methods of Treatment

[00206] Provided herein are methods of treating a subject who has or may be at risk of developing a neurodegenerative disease or disorder by administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.

[00207] In some embodiments, the neurodegenerative disease is associated with modulated activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity, cytokines). In some embodiments, the increased expression, stimulation, proliferation, differentiation, number or activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of T cells activity, cytokines) or a combination thereof is associated with neurodegenerative disease or risk of developing neurodegenerative disease or disorder. In some embodiments, the increased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, is associated with neurodegenerative disease or risk of developing neurodegenerative disease. In some embodiments, the increased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, is associated neurodegenerative disease or risk of developing neurodegenerative disease. In some embodiments, the increased stimulation, differentiation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same) is associated with neurodegenerative disease or risk of developing

neurodegenerative disease or disorder. In some embodiments, the increase production or activity of mediators of immune cell (e.g. T cell or B cell activity) such as cytokines is associated with neurodegenerative disease or disorder or risk of developing

neurodegenerative disease or disorder. In some embodiments, the increase in activity or expression of immune cells or proteins results from an immune response to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, an increased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In particular embodiments, an increased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder.

[00208] In some embodiments, the neurodegenerative disease or disorder is associated with a decreased activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity, cytokines). In some embodiments, the decreased expression of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity, cytokines) or a combination thereof is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In some embodiments, the decreased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In some embodiments, the decreased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In some embodiments, the decreased stimulation, differentiation activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same) is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In some embodiments, the decreased production or activity of mediators of immune cell (e.g. T cell or B cell) activity, for example cytokines, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease. In some embodiments, the decrease in activity or expression of immune cells or proteins results from an immune response to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, a decreased stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In particular embodiments, a decreased stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder.

[00209] In some embodiments, the increased expression or activity of a first immune cell or immune protein and the decreased expression or activity of a second immune cell or immune protein is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder.

[00210] In particular embodiments, a modulation in the expression or activity of autoreactive immune cells (e.g. T cells or B cells) is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In certain embodiments, a modulation in the expression or activity of autoreactive immune cells (e.g. T cells or B cells) that are reactive to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder. In still further embodiments a modulation in the expression or activity of autoantibodies, including for example autoantibodies that bind one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, is associated with neurodegenerative disease or disorder or risk of developing neurodegenerative disease or disorder.

[00211] In some embodiments, the method is a method of treating a subject who has a neurodegenerative disease or disorder by administering to the subject a

therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response. In other embodiments, the method is a method of treating a subject who may be at risk of developing a neurodegenerative disease or disorder by administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.

[00212] Non-limiting example of a neurodegenerative disease or disorder include Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or

Huntington's disease.

[00213] In some embodiments, the agent is an agonist of one or more immune cells or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof. In further embodiment, the agent is an antagonist of one or more immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof. In an additional embodiment, the agent is an agonist for a first immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) and an antagonist for a second immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines). In some embodiments, the agent is an agonist or antagonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines).

[00214] In some embodiments, the method comprises administering to the subject an agonist or antagonist of T cell stimulation, differentiation, activation, proliferation, number or activity, or a combination thereof. In some embodiments, the method comprises administering to the subject an agonist or antagonist of B cell stimulation, differentiation, activation, proliferation, number or activity, or a combination thereof. In some embodiments, the method comprises administering to the subject and agonist or antagonist of activation, proliferation, number or activity, or a combination thereof, of autoreactive immune cells (e.g. B cells or T cells). In certain embodiments, the method comprises administering to the subject and agonist or antagonist of autoreactive immune cells wherein the autoreactive immune cells are reactive to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain, embodiments of the present methods, B cells and/or T cells are completely depleted in the subject. In other embodiments, B cells and/or T cells are partially depleted in a subject. In certain embodiments, autoreactive immune cells are partially or completely deleted in a subject. In some embodiments, autoreactive immune cells that are reactive to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, are partially or completed depleted in a subject.

[00215] In particular embodiments of the present invention, there is provided methods of treatment comprising administering a multimer to deplete immune cells in a subject. In certain embodiments, the methods comprise administering multimers comprising one or more of the peptides listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof, to deplete immune cells (e.g. T cells). In particular embodiments, the methods comprise use of the multimers to deplete immune cells that are specific for a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00216] In further embodiments, the methods of treatment presently described comprises administering to the subject an agonist or antagonist of activation,

differentiation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same). In some embodiments, the method comprises administering to the subject an agonist or antagonist of production or activity, or a combination thereof, of mediators of immune cell activity (e.g. T cell or B cell). In some embodiments, the method comprises administering to the subject an agonist or antagonist of production or activity, or a combination thereof, of cytokines, immune activators, chemokines, growth factors and T F family members (e.g. AREG, Granzyme, Histamine, IFNa/b, IFNg, IL12, IL15, IL16, IL17a-f, ILlb, 112, IL21, IL22, IL23, IL25, IL27, GM-CSF, IL33, IL4, IL5, IL6, IL7, IL8, IL9, LFA-1, LIF, lymphotoxin, Mac-1, MCP-1, MlPla, Perforin, TGF-B, TNFa, VLA-4, CCL1, CCL11, CLL17, CCL1, CCL20, CCL22, CCL3, CCL4, CCL5, CXCL10, CXCL13, CXCL8, RANTES, CXCL12, G-CSF, M-CSF, VEGF, PDGF, 4-1BB, APRIL, BAFF, CD27, CD30, CD30L, CD70, DR3, DR4, DR5, FAS, FASL, GITR, HVEM, LIGHT, LTB, OX40, Ox40L, TACI, TRAIL, TWEAK, IL11, IL14 or IL10).

[00217] In some embodiments, the method comprises administering to the subject an agonist or antagonist of activity or expression of immune cells or immune proteins in response to one or more proteins or peptides of the central nervous system, uch as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the method comprises administering to the subject an agonist or antagonist of an innate immune response. In other embodiments, the method comprises administering to the subject an agonist or antagonist of an adaptive immune response. In particular embodiments, the method comprises administering to the subject an agonist or antagonist of stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In particular embodiments, the method comprises administering to the subject an agonist or antagonist of stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. [00218] In some embodiments, the therapeutic agent is an agonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) types of immune cells or immune proteins. In some embodiments, the therapeutic agent is an antagonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) types of immune cells or immune proteins.

[00219] An agonist is an agent that increases expression, activity and/or one or more functional effects associated with an immune cell or immune protein. An antagonist is an agent that decreases expression, activity and/or one or more functional effects associated with an immune cell or immune protein. The phrase "functional effects" as used herein refers to any parameter that is indirectly or directly under the influence of the immune cell or immune protein, e.g., functional, physical and chemical effects. It includes ligand binding, signal transduction, receptor-ligand interactions, second messenger concentrations, in vitro, in vivo, and ex vivo and also includes other physiologic effects such increases or decreases in immune or inflammatory signals or immune or inflammatory signaling cascades.

[00220] Provided herein are methods of treating a subject who has or may be at risk of developing a neurodegenerative disease. The method including administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response. In some embodiments, the method further includes, prior to said administering, determining whether a subject has an increased or decreased immune response in comparison to a suitable control, including but not limited to increased or decreased immune protein, autoantibody or immune cell expression or activity. In particular embodiments, the method involves determining if the subject has increased or decreased T cell or B cell stimulation, differentiation activation, proliferation or activity or production of autoantibodies or immune cell mediators. In certain embodiments, the method involves determining if the subject has increased or decreased T cell or B cell stimulation, differentiation, activation, proliferation or activity or production of autoantibodies or immune cell mediators in response to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the increased or decreased immune response is an innate immune response. In some embodiments, the increased or decreased immune response is an adaptive immune response.

[00221] In some embodiments, the method further includes administering the agent in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is selected from a disease-modifying drug known in the art, including but not limited drugs for the treatment neurodegenerative diseases.

[00222] In certain embodiments, the subject is administered a combination of agents including known auto-immune, anti-inflammatory or immunosuppressive drugs, (e.g. anti-T F agent, anti-cytokine agent, statin, anti-chemokines, anti-integrins or flavonoids).

[00223] Thus, in certain embodiments, an agent described herein can be administered in combination with a second agent, drug or treatment, such as an anti- autoimmune, anti-inflammatory, immunosuppressive drug or treatment.

[00224] Agents as described herein, can be used alone, sequentially, or in combination according to the methods described herein. In some embodiments, agent is used in combination with one or more other drug or treatment, e.g. agonist or antagonist of an immune protein or immune cell, anti-inflammatory or immunosuppressive agent.

[00225] In certain embodiments, the subject is administered a pharmaceutical composition as described herein. In particular embodiments, the subject is administered one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. The subject may be administered one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, in order to modulate immune response to the one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same, including for example, inducing immune tolerance in the subject against the one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. Such methods would incorporate methods comparable to those known in the art for antigen-specific immunotherapy.

[00226] In particular embodiments, the method or composition comprises two or more proteins, peptides or epitopes including but not limited to proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the method or composition comprises peptides or epitopes derived from two or more of the proteins listed in Table 1 or 2. In different embodiments, the method or composition comprises peptides or epitopes from two or more, three or more, four or more, or five different proteins listed in Table 1 or 2 or peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof.

[00227] As each T cell epitope binds only a subset of naturally occurring HLA Class II molecules in the human population and this repertoire of HLA Class II molecules varies from one person to another and from one ethnic population to another, in certain embodiments of the presentation invention, it is desirable to select a mix of several peptides covering different HLA Class II molecules to generate an immune response in a broad segment of the population. Further, in other embodiments of the present invention, it is desirable to select peptides that elicit an immune response (e.g. T cell response or an immune response (e.g. T cell response) in a significant fraction of subjects. Thus, in particular embodiments, it is desirable to select an epitope or combination of epitopes that have a HLA Class II repertoire covering a high fraction of a worldwide population, which also produce an immune response (e.g. T cell response) and which also produce an immune response (e.g. T cell response) in a significant fraction of subjects with the disease, disorder or condition to be treated. In certain embodiments the epitopes are selected that bind the HLA alleles listed in Tables 103 and 104.

[00228] In particular embodiments, it is desirable for the methods or compositions of the present invention to include as few peptides as possible, but at the same time to be able to treat the majority of patients in a worldwide population with the same method or composition. Such a method or composition should contain a combination of peptides capable of binding to a HLA Class II repertoire covering a high fraction of a worldwide population, and the resulting peptide-HLA complexes should be recognized as epitopes (e.g. T cell epitopes) in the subject so as to induce an immune response.

[00229] In certain embodiments, the methods of treatment presently described comprise administering an agent that blocks binding of an autoantibody to a protein or peptide in the subject. In certain embodiments, the methods of treatment presently described comprise administering an agent that blocks binding of an autoantibody to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00230] In certain embodiments, the methods of treatment presently described comprises administering an antibody that blocks binding of an autoantibody to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the antibody administered is an antibody that does not elicit an immune response, including, for example, an antibody that has been engineered such that it does not elicit an immune response in a subject. In certain embodiments, the antibody administered competes with autoantibodies for binding to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00231] In other embodiments, the methods of treatment presently described comprises administering an antibody fragment or derivative (e.g. Fab) that blocks binding of an autoantibody to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the antibody fragment or derivative administered competes with autoantibodies for binding to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00232] Pharmaceutical compositions

[00233] Provided herein are pharmaceutical compositions for treating a subject who has or may be at risk of developing a neurodegenerative disease or disorder and methods for treating a subject who has or may be at risk of developing a neurodegenerative disease or disorder by administering the pharmaceutical compositions described herein to the subject. In certain embodiments, the pharmaceutical

compositions described herein comprise a therapeutically effective amount of an agent as described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions are for treating a subject who has a neurodegenerative disease or disorder by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions are for treating a subject who may be at risk of developing neurodegenerative disease or disorder by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent and a pharmaceutically acceptable excipient. In some embodiments, the associated disease or disorder comprises Parkinson's disease, vascular dementia, early onset dementia, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, corticobasal syndrome, lewy body disease, frontotemporal dementia, motor neuron disease, progressive supranulear palsy, multiple system atrophy, multiple sclerosis, myasthenia gravis, and/or Huntington's disease.

[00234] In some embodiments, the pharmaceutical composition comprises an agent that is a therapeutic agent. In particular embodiments, the therapeutic agent is an antibody, antibody derivative (e.g. Fab), protein, peptide, nucleic acid, synthetic chemical, small chemical molecule, or ligand mimetic. In certain embodiments, the therapeutic agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response. In some embodiments, the therapeutic agent modulates stimulation, activation proliferation, number or activity of immune proteins or cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity, antibodies etc.) In certain embodiments, the therapeutic agent modulates an innate immune response. In certain embodiments, the therapeutic agent modulates an adaptive immune response. In particular embodiments, the therapeutic agent modulates an immune response to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00235] In particular aspects the therapeutic agent when administered to a subject treats a neurodegenerative disease or disorder when administered to a subject in a therapeutically effective dose or amount. In some embodiments, the therapeutic agent is an agent that binds one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same (e.g. an antibody or a Fab).

[00236] In certain embodiments, the therapeutic agent disrupts the interaction between an immune cell or immune protein and a physiological or natural ligand. In some embodiments, the therapeutic agent binds a physiological or natural ligand of the immune cell or immune protein. In some embodiments, the therapeutic agent binds the complex an immune cell or immune protein bound to a ligand. In some embodiments, the therapeutic agent disrupts the interaction between an immune cell or immune protein and one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the therapeutic agent binds an immune cell or immune protein that interacts with one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some

embodiments, the therapeutic agent binds one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell,for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the therapeutic agent binds the complex of an immune cell or immune protein bound to one or more of proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In some embodiments, the therapeutic agent binds a mediator of immune cell activity (e.g. cytokines, immune activators, chemokines, growth factors and T F family members).

[00237] In more specific embodiments, the therapeutic agent modulates the activity or expression of one or more type of immune cell or protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof. In some embodiments, the therapeutic agent modulates the stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof. In some embodiments, the therapeutic agent modulates the stimulation of B cells, differentiation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof. In some embodiments, the therapeutic agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same). In some embodiments, the therapeutic agent modulates the expression or activity of autoantibodies (e.g. autoantibodies to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same). In some embodiments, the therapeutic agent completely or partially depletes immune cells in the subject (e.g. B cells or T cells). In some

embodiments, the therapeutic agent completely or partially deletes autoreactive immune cells. In some embodiments, the therapeutic agent completely or partially depletes autoreactive immune cells that are reactive to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00238] In some embodiments, the therapeutic agent modulates production or activity of mediators of immune cell activity, including T cell and/or B cell activity, including e.g. cytokines, immune activators, chemokines, growth factors and T F family members (e.g. AREG, Granzyme, Histamine, IFNa/b, IFNg, IL12, IL15, IL16, IL17a-f, ILlb, 112, IL21, IL22, IL23, IL25, IL27, GM-CSF, IL33, IL4, IL5, IL6, IL7, IL8, IL9, LFA-1, LIF, lymphotoxin, Mac-1, MCP-1, MlPla, Perforin, TGF-B, TNF a, VLA-4, CCL1, CCL11, CLL17, CCL1, CCL20, CCL22, CCL3, CCL4, CCL5, CXCL10, CXCL13, CXCL8, RANTES, CXCL12, G-CSF, M-CSF, VEGF, PDGF, 4-lBB, APRIL, BAFF, CD27, CD30, CD30L, CD70, DR3, DR4, DR5, FAS, FASL, GITR, HVEM, LIGH). In some embodiments, the therapeutic agent modulates activity or expression of immune cells or proteins involved in an immune response to one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In certain embodiments, the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response. In particular embodiments, the therapeutic agent modulates stimulation of T cells, activation of T cells, differentiation of T cells proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In particular embodiments, the therapeutic agent modulates stimulation of B cells, activation of B cells, differentiation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a

modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. In particular embodiments, the therapeutic agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies.

[00239] In some embodiments, the therapeutic agent is an agonist of one or more immune cells or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity) or a combination thereof. In further

embodiment, the therapeutic agent is an antagonist of one or more immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity) or a combination thereof. In an additional

embodiment, the therapeutic agent is an agonist for a first immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity) and an antagonist for a second immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity). In some embodiments, the therapeutic agent is an antagonist or agonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) types of immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, mediators of immune cell activity).

[00240] In some embodiments, the therapeutic agent is selected from a protein, peptide, modified protein, modified peptide, antibody, antibody derivative (Fab), an inhibitory nucleic acid, a ligand mimetic or a small molecule. In some embodiments, the therapeutic agent is a Fab. Thus, in particular embodiments, the pharmaceutical composition includes a Fab and a pharmaceutically acceptable excipient. In particular embodiments, the pharmaceutical composition include a Fab that binds one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same.

[00241] In some embodiments, the therapeutic agent is an anti-inflammatory or immunosuppressive drugs, (e.g. anti-TNF agent, anti-cytokine agent, statin, anti- chemokines, anti-integrins or flavonoids). In certain embodiments, the therapeutic agents is Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Ezetimibe/simvastatin, Pitavastatin, Cerivastatin, Mevastatin, Atorvastatin/amlodipine, Niacin/simvastatin, Niacin/lovastatin, Simvastatin/sitagliptin, 3,6'-dithiothalidomide, Enzogenol,

Tocilizumab, Rituximab, Ofatumumab, Belimumab, Epratuzumab, Abatacept,

Golimumab, Certolizumab, Sifalimumab, Intravenous immunoglobulin, Glatiramer acetate, Natalizumab, Infliximab, Enbrel, Humira, Eculizuma, Ixekizumab, Brodalumab, Secukinumab, Ustekinumab, AMG 811, Alemtuzumab, Dimethyl fumarate, fingolimod, ocrelizumab, ofatumumab, Anakinra, canakinumab, rilonocept, Rapamycin,

cyclosporine, tofactinib, tubastatin, prednisone, methyltrexate, Medrol, hydrocortisone, veripred, celestone souluspan, kenalog).

[00242] In some embodiments, the pharmaceutical composition is useful for treating for treating a subject who has or may be at risk of developing a

neurodegenerative disease. In some embodiments, the pharmaceutical compositions are useful for treating a subject who has or may be at risk of developing a neurodegenerative disease by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response and a pharmaceutically acceptable excipient.

[00243] The compositions disclosed herein can be administered by any means known in the art. For example, compositions may include administration to a subject intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intrathecally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion, via a catheter, via a lavage, via a dermal patch, in a cream, or in a lipid composition.

Administration can be local or systemic.

[00244] Solutions of the active compounds as free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid

polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[00245] Pharmaceutical compositions can be delivered via intranasal or inhalable solutions or sprays, aerosols or inhalants. Nasal solutions can be aqueous solutions designed to be administered to the nasal passages in drops or sprays. Nasal solutions can be prepared so that they are similar in many respects to nasal secretions. Thus, the aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5. In addition, antimicrobial preservatives, similar to those used in ophthalmic preparations, and appropriate drug stabilizers, if required, may be included in the formulation. Various commercial nasal preparations are known and can include, for example, antibiotics and antihistamines.

[00246] Oral formulations can include excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In some embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%. The amount of active compounds in such compositions is such that a suitable dosage can be obtained.

[00247] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions, in particular, sterile aqueous media, are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion.

[00248] Sterile injectable solutions can be prepared by incorporating the active compounds or constructs in the required amount in the appropriate solvent followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium. Vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredients, can be used to prepare sterile powders for reconstitution of sterile injectable solutions. The preparation of more, or highly, concentrated solutions for direct injection is also contemplated. DMSO can be used as solvent for extremely rapid penetration, delivering high concentrations of the active agents to a small area.

[00249] The invention provides methods of treating, preventing, and/or ameliorating a neurodegenerative disease or disorder in a subject in need thereof. The course of treatment is best determined on an individual basis depending on the particular characteristics of the subject and the type of treatment selected. The treatment, such as those disclosed herein, can be administered to the subject on a daily, twice daily, biweekly, monthly or any applicable basis that is therapeutically effective. The treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art. The additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).

[00250] Administration of a composition for treating a neurodegenerative disease or disorder (e.g., by treating modulated immune response, including for example immune response to one or more of proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same) can be a systemic or localized administration. For example, treating a subject having a neurodegenerative disease or disorder can include administering an oral or injectable form of a therapeutic agent as described herein on a daily basis or otherwise regular schedule.

[00251] In certain embodiments, the pharmaceutical composition is administered to the subject prior to development of a neurodegenerative disease. In other

embodiments, the pharmaceutical composition is administered to the subject after development of a neurodegenerative disease.

[00252] Epitope Combinations

[00253] In certain embodiments, the methods and compositions presently provided for treating a subject who has a neurodegenerative disease or disorder comprise administering an optimized package comprising one or more antigens. In particular embodiments, the optimized package includes one or more epitopes from an antigen that elicits an immune response in a neurodegenerative disease e.g. one or more proteins or peptides of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. In specific embodiments, the optimized package comprises one or more CD4 or CD8 T cell epitopes, for example, one or more of the epitopes listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the optimized package contains epitopes selected for their broad recognition by HLA molecules of subjects from diverse ethnic and geographically backgrounds. Thus in different embodiments, the method and compositions of the present invention comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty of more of the peptides listed in any of Tables 3 to 102, or a

modification, subsequence, homologue, variant or derivative thereof. In different embodiments, the peptides are derived from one or more different proteins, including for example the proteins listed in Table 1 or 2, or a modification, subsequence, homologue, variant or derivative thereof.

[00254] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[00255] All applications, publications, patents and other references, GenBank citations and ATCC citations cited herein are incorporated by reference in their entirety. In case of conflict, the specification, including definitions, will control.

[00256] All of the features disclosed herein may be combined in any combination. Each feature disclosed in the specification may be replaced by an alternative feature serving a same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, disclosed features (e.g., compound structures) are an example of a genus of equivalent or similar features.

[00257] As used herein, the singular forms "a", "and," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a first, second, third, fourth, fifth, etc. predictor gene" or a "positive or negative predictor gene" includes a plurality of such first, second, third, fourth, fifth, etc., genes, or a plurality of positive and/or negative predictor genes. [00258] As used herein, all numerical values or numerical ranges include integers within such ranges and fractions of the values or the integers within ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.

[00259] Reference to a number with more (greater) or less than includes any number greater or less than the reference number, respectively. Thus, for example, a reference to less than 30,000, includes 29,999, 29,998, 29,997, etc. all the way down to the number one (1); and less than 20,000, includes 19,999, 19,998, 19,997, etc. all the way down to the number one (1).

[00260] As used herein, all numerical values or ranges include fractions of the values and integers within such ranges and fractions of the integers within such ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a numerical range, such as a percentage range, 90-100%), includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. Reference to a range ofl-5 fold therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.

[00261] Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series. Thus, to illustrate reference to a series of ranges of 2-72 hours, 2-48 hours, 4-24 hours, 4-18 hours and 6-12 hours, includes ranges of 2-6 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.

[00262] The invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects. The invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures. For example, in certain embodiments or aspects of the invention, materials and/or method steps are excluded. Thus, even though the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.

[00263] A number of embodiments of the invention have been described.

Nevertheless, one skilled in the art, without departing from the spirit and scope of the invention, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, the following examples are intended to illustrate but not limit the scope of the invention claimed.

[00264] EXAMPLES

[00265] Detection of T cell and B cell Reactivity

[00266] A blood sample is obtained from a subject that is believed to have or be at risk of developing a neurodegenerative disease or disorder. T cells and B cells are isolated from the blood of the individual. The cells are plated with one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a modification, subsequence, homologue, variant or derivative thereof and reactivity of the T cells and/or B cells is measured e.g. through measurement of T cell and/or B cell proliferation, cytokine production etc.

[00267] Detection of Modified Proteins or Peptides or Immune Cell Mediators

[00268] In combination or separately from the measurement of T cell and B cell activity, the blood sample is optionally exposed to antibodies that detect modified proteins derived from glial or neuronal cell, modified forms one or more of the proteins listed in Table 1 or 2, modified forms one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof or the presence of mediators of immune cell activity and the level of expression of such modified proteins, peptides, or mediators of immune cell activity is measured by methods known in the art.

[00269] Detection of Autoantibodies [00270] In combination or separately from the measurement of T cell and B cell activity, to determine if a subject has autoantibodies to a protein of the central nervous system (e.g. proteins listed in Table 1 or 2) or a modification, subsequence, homologue, variant or derivative thereof, the blood sample is exposed to a one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102, or a subsequence, homologue, variant or derivative thereof and the binding of antibodies in the sample to such proteins or peptides is measured by methods known in the art.

[00271] Generation and administration of antibodies and Fabs

[00272] The activation of the adaptive immune system is inhibited through the administration of an antibody or antibody derivative (e.g. Fab) targeted against a protein or peptide of the central nervous system, such as a protein or peptide derived from a glial or neuronal cell, for example one or more of the proteins listed in Table 1 or 2, one or more of the peptides listed in any of Tables 3 to 102 or a modification, subsequence, homologue, variant or derivative thereof, or protein plaques or tangles comprising the same. These antibodies or antibody derivatives may compete or inhibit autoantibody binding to these proteins and peptides. The antibodies and antibody derivatives are administered to the subject and bind the relevant proteins or peptides to inhibit autoantibody binding and/or block T cells and B cells from becoming activated by proteins or peptides.