Modeling the heterogeneity of multiple sclerosis in animals

Trends in Immunology - Tập 34 - Trang 410-422 - 2013
Sarah B. Simmons1, Emily R. Pierson1, Sarah Y. Lee1, Joan M. Goverman1
1Department of Immunology, University of Washington, Seattle, WA 98195, USA

Tài liệu tham khảo

Sawcer, 2011, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis, Nature, 476, 214, 10.1038/nature10251 Gay, 1997, The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion, Brain, 120, 1461, 10.1093/brain/120.8.1461 Babbe, 2000, Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction, J. Exp. Med., 192, 393, 10.1084/jem.192.3.393 Noseworthy, 2000, Multiple sclerosis, N. Engl. J. Med., 343, 938, 10.1056/NEJM200009283431307 Lassmann, 2012, Progressive multiple sclerosis: pathology and pathogenesis, Nat. Rev. Neurol., 8, 647, 10.1038/nrneurol.2012.168 Lucchinetti, 2000, Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination, Ann. Neurol., 47, 707, 10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-Q Rodriguez, 2007, Effectors of demyelination and remyelination in the CNS: implications for multiple sclerosis, Brain Pathol., 17, 219, 10.1111/j.1750-3639.2007.00065.x Probert, 1995, Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha, Proc. Natl. Acad. Sci. U.S.A., 92, 11294, 10.1073/pnas.92.24.11294 Campbell, 1998, Structural and functional impact of the transgenic expression of cytokines in the CNS, Ann. N. Y. Acad. Sci., 840, 83, 10.1111/j.1749-6632.1998.tb09552.x Buch, 2005, A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration, Nat. Methods, 2, 419, 10.1038/nmeth762 Traka, 2010, A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination, Brain, 133, 3017, 10.1093/brain/awq247 Stromnes, 2006, Passive induction of experimental allergic encephalomyelitis, Nat. Protoc., 1, 1952, 10.1038/nprot.2006.284 Stromnes, 2006, Active induction of experimental allergic encephalomyelitis, Nat. Protoc., 1, 1810, 10.1038/nprot.2006.285 Goverman, 1999, Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein, Immunol. Rev., 169, 147, 10.1111/j.1600-065X.1999.tb01313.x Krishnamoorthy, 2007, Experimental models of spontaneous autoimmune disease in the central nervous system, J. Mol. Med., 85, 1161, 10.1007/s00109-007-0218-x Miller, 2012, Clinically isolated syndromes, Lancet Neurol., 11, 157, 10.1016/S1474-4422(11)70274-5 Giovannoni, 2004, Management of secondary-progressive multiple sclerosis, CNS Drugs, 18, 653, 10.2165/00023210-200418100-00003 Weinshenker, 1989, The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course, Brain, 112, 1419, 10.1093/brain/112.6.1419 Thompson, 1997, Primary progressive multiple sclerosis, Brain, 120, 1085, 10.1093/brain/120.6.1085 Lassmann, 2007, The immunopathology of multiple sclerosis: an overview, Brain Pathol., 17, 210, 10.1111/j.1750-3639.2007.00064.x Thorpe, 1996, Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI, Brain, 119, 709, 10.1093/brain/119.3.709 Nociti, 2005, Clinical characteristics, course and prognosis of spinal multiple sclerosis, Spinal Cord, 43, 731, 10.1038/sj.sc.3101798 Lennon, 2004, A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis, Lancet, 364, 2106, 10.1016/S0140-6736(04)17551-X Lassmann, 2003, Hypoxia-like tissue injury as a component of multiple sclerosis lesions, J. Neurol. Sci., 206, 187, 10.1016/S0022-510X(02)00421-5 Barnett, 2004, Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion, Ann. Neurol., 55, 458, 10.1002/ana.20016 Breij, 2008, Homogeneity of active demyelinating lesions in established multiple sclerosis, Ann. Neurol., 63, 16, 10.1002/ana.21311 Bruck, 2012, Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate, Ann. Neurol., 72, 385, 10.1002/ana.23621 Koritschoner, 1925, Induktion von Paralyse und Rückenmarksentzündung durch Immunisierung von Kaninchen mit menschlichem Rückenmarksgewebe, Z. Immunitätsf Exp. Ther., 42, 217 Paterson, 1960, Transfer of allergic encephalomyelitis in rats by means of lymph node cells, J. Exp. Med., 111, 119, 10.1084/jem.111.1.119 Zamvil, 1990, The T lymphocyte in experimental allergic encephalomyelitis, Annu. Rev. Immunol., 8, 579, 10.1146/annurev.iy.08.040190.003051 Mendel, 1995, A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells, Eur. J. Immunol., 25, 1951, 10.1002/eji.1830250723 Goverman, 1993, Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity, Cell, 72, 551, 10.1016/0092-8674(93)90074-Z Lafaille, 1994, High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice, Cell, 78, 399, 10.1016/0092-8674(94)90419-7 Waldner, 2000, Fulminant spontaneous autoimmunity of the central nervous system in myelin proteolipid protein specific T cell receptor transgenic mice, Proc. Natl. Acad. Sci. U.S.A., 97, 3412, 10.1073/pnas.97.7.3412 Bettelli, 2003, Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis, J. Exp. Med., 197, 1073, 10.1084/jem.20021603 Liu, 1995, Low avidity recognition of self-antigen by T cells permits escape from central tolerance, Immunity, 3, 407, 10.1016/1074-7613(95)90170-1 Sospedra, 2005, Immunology of multiple sclerosis, Annu. Rev. Immunol., 23, 683, 10.1146/annurev.immunol.23.021704.115707 Baron, 1993, Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma, J. Exp. Med., 177, 57, 10.1084/jem.177.1.57 Segal, 1996, IL-12 unmasks latent autoimmune disease in resistant mice, J. Exp. Med., 184, 771, 10.1084/jem.184.2.771 Bettelli, 2004, Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis, J. Exp. Med., 200, 79, 10.1084/jem.20031819 Becher, 2002, Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12, J. Clin. Invest., 110, 493, 10.1172/JCI0215751 Cua, 2003, Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain, Nature, 421, 744, 10.1038/nature01355 Langrish, 2005, IL-23 drives a pathogenic T cell population that induces autoimmune inflammation, J. Exp. Med., 201, 233, 10.1084/jem.20041257 Jager, 2009, Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes, J. Immunol., 183, 7169, 10.4049/jimmunol.0901906 Traugott, 1988, Multiple sclerosis: involvement of interferons in lesion pathogenesis, Ann. Neurol., 24, 243, 10.1002/ana.410240211 Link, 1992, Virus-reactive and autoreactive T cells are accumulated in cerebrospinal fluid in multiple sclerosis, J. Neuroimmunol., 38, 63, 10.1016/0165-5728(92)90091-X Kebir, 2007, Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation, Nat. Med., 13, 1173, 10.1038/nm1651 Lock, 2002, Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis, Nat. Med., 8, 500, 10.1038/nm0502-500 Brucklacher-Waldert, 2009, Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis, Brain, 132, 3329, 10.1093/brain/awp289 Kroenke, 2008, IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition, J. Exp. Med., 205, 1535, 10.1084/jem.20080159 Stromnes, 2008, Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells, Nat. Med., 14, 337, 10.1038/nm1715 Domingues, 2010, Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis, PLoS ONE, 5, e15531, 10.1371/journal.pone.0015531 Abromson-Leeman, 2009, Encephalitogenic T cells that stably express both T-bet and ROR gamma t consistently produce IFNgamma but have a spectrum of IL-17 profiles, J. Neuroimmunol., 215, 10, 10.1016/j.jneuroim.2009.07.007 Peters, 2011, The many faces of Th17 cells, Curr. Opin. Immunol., 23, 702, 10.1016/j.coi.2011.08.007 Kurschus, 2010, Genetic proof for the transient nature of the Th17 phenotype, Eur. J. Immunol., 40, 3336, 10.1002/eji.201040755 Kebir, 2009, Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis, Ann. Neurol., 66, 390, 10.1002/ana.21748 Hirota, 2011, Fate mapping of IL-17-producing T cells in inflammatory responses, Nat. Immunol., 12, 255, 10.1038/ni.1993 Ferber, 1996, Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE), J. Immunol., 156, 5, 10.4049/jimmunol.156.1.5 Wensky, 2005, IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis, J. Immunol., 174, 1416, 10.4049/jimmunol.174.3.1416 Panitch, 1987, Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system, Neurology, 37, 1097, 10.1212/WNL.37.7.1097 Haak, 2009, IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice, J. Clin. Invest., 119, 61 Hofstetter, 2005, Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis, Cell. Immunol., 237, 123, 10.1016/j.cellimm.2005.11.002 Komiyama, 2006, IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis, J. Immunol., 177, 566, 10.4049/jimmunol.177.1.566 Gonzalez-Garcia, 2009, IL-17 signaling-independent central nervous system autoimmunity is negatively regulated by TGF-beta, J. Immunol., 182, 2665, 10.4049/jimmunol.0802221 Hu, 2010, IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis, J. Immunol., 184, 4307, 10.4049/jimmunol.0903614 E. Havrdová, 2012, Late breaking news 2: positive proof of concept of AIN457, an antibody against interleukin-17A, in relapsing-remitting multiple sclerosis, Mult. Scler. J., 18, 513 McQualter, 2001, Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis, J. Exp. Med., 194, 873, 10.1084/jem.194.7.873 Ponomarev, 2007, GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis, J. Immunol., 178, 39, 10.4049/jimmunol.178.1.39 El-Behi, 2011, The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF, Nat. Immunol., 12, 568, 10.1038/ni.2031 Codarri, 2011, RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation, Nat. Immunol., 12, 560, 10.1038/ni.2027 Carrieri, 1998, Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: a correlation with clinical activity, Immunopharmacol. Immunotoxicol., 20, 373, 10.3109/08923979809034820 Olivares-Villagomez, 1998, Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis, J. Exp. Med., 188, 1883, 10.1084/jem.188.10.1883 Kohm, 2002, Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis, J. Immunol., 169, 4712, 10.4049/jimmunol.169.9.4712 Reddy, 2004, Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis, Proc. Natl. Acad. Sci. U.S.A., 101, 15434, 10.1073/pnas.0404444101 Zhang, 2004, IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells, Int. Immunol., 16, 249, 10.1093/intimm/dxh029 Liu, 2006, Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE, Nat. Med., 12, 518, 10.1038/nm1402 Korn, 2007, Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation, Nat. Med., 13, 423, 10.1038/nm1564 McGeachy, 2005, Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system, J. Immunol., 175, 3025, 10.4049/jimmunol.175.5.3025 Allan, 2008, CD4+ T-regulatory cells: toward therapy for human diseases, Immunol. Rev., 223, 391, 10.1111/j.1600-065X.2008.00634.x Frisullo, 2009, Regulatory T cells fail to suppress CD4T+-bet+ T cells in relapsing multiple sclerosis patients, Immunology, 127, 418, 10.1111/j.1365-2567.2008.02963.x Viglietta, 2004, Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis, J. Exp. Med., 199, 971, 10.1084/jem.20031579 Haas, 2005, Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis, Eur. J. Immunol., 35, 3343, 10.1002/eji.200526065 Dominguez-Villar, 2011, Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease, Nat. Med., 17, 673, 10.1038/nm.2389 Baranzini, 2009, The genetics of autoimmune diseases: a networked perspective, Curr. Opin. Immunol., 21, 596, 10.1016/j.coi.2009.09.014 Zenewicz, 2010, Unraveling the genetics of autoimmunity, Cell, 140, 791, 10.1016/j.cell.2010.03.003 Broux, 2010, Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants, Genes Immun., 11, 326, 10.1038/gene.2009.106 De Jager, 2009, Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci, Nat. Genet., 41, 776, 10.1038/ng.401 de Andres, 2007, Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis, J. Neuroimmunol., 182, 204, 10.1016/j.jneuroim.2006.09.012 Korporal, 2008, Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells, Arch. Neurol., 65, 1434, 10.1001/archneur.65.11.1434 Kabat, 1948, Quantitative estimation of the albumin and gamma globulin in normal and pathologic cerebrospinal fluid by immunochemical methods, Am. J. Med., 4, 653, 10.1016/S0002-9343(48)90389-1 Owens, 2001, The immunoglobulin G heavy chain repertoire in multiple sclerosis plaques is distinct from the heavy chain repertoire in peripheral blood lymphocytes, Clin. Immunol., 98, 258, 10.1006/clim.2000.4967 Ligocki, 2010, A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis, J. Neuroimmunol., 226, 192, 10.1016/j.jneuroim.2010.06.016 Lovato, 2011, Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis, Brain, 134, 534, 10.1093/brain/awq350 Obermeier, 2011, Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin, J. Neuroimmunol., 233, 245, 10.1016/j.jneuroim.2011.01.010 Wolf, 1996, Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice, J. Exp. Med., 184, 2271, 10.1084/jem.184.6.2271 Oliver, 2003, Rat and human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice, J. Immunol., 171, 462, 10.4049/jimmunol.171.1.462 Lyons, 1999, B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide, Eur. J. Immunol., 29, 3432, 10.1002/(SICI)1521-4141(199911)29:11<3432::AID-IMMU3432>3.0.CO;2-2 Weber, 2010, B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity, Ann. Neurol., 68, 369, 10.1002/ana.22081 Fillatreau, 2002, B cells regulate autoimmunity by provision of IL-10, Nat. Immunol., 3, 944, 10.1038/ni833 Matsushita, 2008, Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression, J. Clin. Invest., 118, 3420 Bettelli, 2006, Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice, J. Clin. Invest., 116, 2393, 10.1172/JCI28334 Krishnamoorthy, 2006, Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation, J. Clin. Invest., 116, 2385, 10.1172/JCI28330 Pollinger, 2009, Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells, J. Exp. Med., 206, 1303, 10.1084/jem.20090299 Berer, 2011, B cells in spontaneous autoimmune diseases of the central nervous system, Mol. Immunol., 48, 1332, 10.1016/j.molimm.2010.10.025 Hauser, 2008, B-cell depletion with rituximab in relapsing-remitting multiple sclerosis, N. Engl. J. Med., 358, 676, 10.1056/NEJMoa0706383 Barr, 2012, B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells, J. Exp. Med., 209, 1001, 10.1084/jem.20111675 Duddy, 2007, Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis, J. Immunol., 178, 6092, 10.4049/jimmunol.178.10.6092 Bar-Or, 2010, Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?, Ann. Neurol., 67, 452, 10.1002/ana.21939 Brabb, 1997, Triggers of autoimmune disease in a murine T-cell receptor transgenic model for multiple sclerosis, J. Immunol., 159, 497, 10.4049/jimmunol.159.1.497 Lee, 2011, Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis, Proc. Natl. Acad. Sci. U.S.A., 108, 4615, 10.1073/pnas.1000082107 Lampropoulou, 2008, TLR-activated B cells suppress T cell-mediated autoimmunity, J. Immunol., 180, 4763, 10.4049/jimmunol.180.7.4763 Berer, 2011, Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination, Nature, 479, 538, 10.1038/nature10554 Macpherson, 2004, Interactions between commensal intestinal bacteria and the immune system, Nat. Rev. Immunol., 4, 478, 10.1038/nri1373 Ochoa-Reparaz, 2009, Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis, J. Immunol., 183, 6041, 10.4049/jimmunol.0900747 Ochoa-Reparaz, 2010, Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora, Gut Microbes, 1, 103, 10.4161/gmic.1.2.11515 Ochoa-Reparaz, 2010, Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression, J. Immunol., 185, 4101, 10.4049/jimmunol.1001443 Lavasani, 2010, A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells, PLoS ONE, 5, e9009, 10.1371/journal.pone.0009009 McRae, 1995, Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis, J. Exp. Med., 182, 75, 10.1084/jem.182.1.75 McMahon, 2005, Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis, Nat. Med., 11, 335, 10.1038/nm1202 Tuohy, 1998, The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis, Immunol. Rev., 164, 93, 10.1111/j.1600-065X.1998.tb01211.x Vanderlugt, 1998, The functional significance of epitope spreading and its regulation by co-stimulatory molecules, Immunol. Rev., 164, 63, 10.1111/j.1600-065X.1998.tb01208.x Vanderlugt, 2000, Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis, J. Immunol., 164, 670, 10.4049/jimmunol.164.2.670 Katz-Levy, 1999, Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice, J. Clin. Invest., 104, 599, 10.1172/JCI7292 Tompkins, 2002, Theiler's virus-mediated autoimmunity: local presentation of CNS antigens and epitope spreading, Ann. N. Y. Acad. Sci., 958, 26, 10.1111/j.1749-6632.2002.tb02944.x Kroenke, 2007, Th17 and Th1 responses directed against the immunizing epitope, as opposed to secondary epitopes, dominate the autoimmune repertoire during relapses of experimental autoimmune encephalomyelitis, J. Neurosci. Res., 85, 1685, 10.1002/jnr.21291 Li, 2011, T cells that trigger acute experimental autoimmune encephalomyelitis also mediate subsequent disease relapses and predominantly produce IL-17, J. Neuroimmunol., 230, 26, 10.1016/j.jneuroim.2010.08.007 Berard, 2010, Characterization of relapsing-remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice, Glia, 58, 434 Peiris, 2007, A model of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice for the characterisation of intervention therapies, J. Neurosci. Methods, 163, 245, 10.1016/j.jneumeth.2007.03.013 Hampton, 2008, An experimental model of secondary progressive multiple sclerosis that shows regional variation in gliosis, remyelination, axonal and neuronal loss, J. Neuroimmunol., 201–202, 200, 10.1016/j.jneuroim.2008.05.034 Basso, 2008, Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis, J. Clin. Invest., 118, 1532, 10.1172/JCI33464 Al-Izki, 2011, Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis, Mult. Scler., 17, 939, 10.1177/1352458511400476 Pryce, 2005, Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis, J. Neuroimmunol., 165, 41, 10.1016/j.jneuroim.2005.04.009 Farez, 2009, Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE, Nat. Immunol., 10, 958, 10.1038/ni.1775 Lees, 2008, Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis, J. Exp. Med., 205, 2633, 10.1084/jem.20080155 Kroenke, 2010, EAE mediated by a non-IFN-gamma/non-IL-17 pathway, Eur. J. Immunol., 40, 2340, 10.1002/eji.201040489 Abromson-Leeman, 2004, T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis, Am. J. Pathol., 165, 1519, 10.1016/S0002-9440(10)63410-4 Tran, 2000, IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines, J. Immunol., 164, 2759, 10.4049/jimmunol.164.5.2759 Willenborg, 1996, IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis, J. Immunol., 157, 3223, 10.4049/jimmunol.157.8.3223 Greer, 1996, Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein, J. Immunol., 156, 371, 10.4049/jimmunol.156.1.371 Komoly, 2005, Experimental demyelination caused by primary oligodendrocyte dystrophy. Regional distribution of the lesions in the nervous system of mice [corrected], Ideggyogy. Sz., 58, 40 Liu, 2010, CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis, Nat. Neurosci., 13, 319, 10.1038/nn.2491 Rodriguez, 1985, Virus-induced demyelination in mice: “dying back” of oligodendrocytes, Mayo Clin. Proc., 60, 433, 10.1016/S0025-6196(12)60865-9 Huseby, 2001, A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis, J. Exp. Med., 194, 669, 10.1084/jem.194.5.669 Friese, 2009, Pathogenic CD8(+) T cells in multiple sclerosis, Ann. Neurol., 66, 132, 10.1002/ana.21744 Goverman, 2009, Autoimmune T cell responses in the central nervous system, Nat. Rev. Immunol., 9, 393, 10.1038/nri2550 Mars, 2011, Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models, Biochim. Biophys. Acta, 1812, 151, 10.1016/j.bbadis.2010.07.006 Woodroofe, 1986, Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis. Possible role for microglia in lesion growth, J. Neurol. Sci., 74, 135, 10.1016/0022-510X(86)90100-0 Hauser, 1986, Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions, Ann. Neurol., 19, 578, 10.1002/ana.410190610 Monteiro, 1995, Clonal dominance of CD8+ T-cell in multiple sclerosis, Ann. N. Y. Acad. Sci., 756, 310, 10.1111/j.1749-6632.1995.tb44529.x Skulina, 2004, Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood, Proc. Natl. Acad. Sci. U.S.A., 101, 2428, 10.1073/pnas.0308689100 Jacobsen, 2002, Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients, Brain, 125, 538, 10.1093/brain/awf059 Junker, 2007, Multiple sclerosis: T-cell receptor expression in distinct brain regions, Brain, 130, 2789, 10.1093/brain/awm214 Zang, 2004, Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis, J. Immunol., 172, 5120, 10.4049/jimmunol.172.8.5120 Crawford, 2004, High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay, Blood, 103, 4222, 10.1182/blood-2003-11-4025 Bitsch, 2000, Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation, Brain, 123, 1174, 10.1093/brain/123.6.1174 Neumann, 2002, Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases, Trends Neurosci., 25, 313, 10.1016/S0166-2236(02)02154-9 Coles, 2006, The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy, J. Neurol., 253, 98, 10.1007/s00415-005-0934-5 Jiang, 1992, Role of CD8+ T cells in murine experimental allergic encephalomyelitis, Science, 256, 1213, 10.1126/science.256.5060.1213 Koh, 1992, Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice, Science, 256, 1210, 10.1126/science.256.5060.1210 Montero, 2004, Regulation of experimental autoimmune encephalomyelitis by CD4+, CD25+ and CD8+ T cells: analysis using depleting antibodies, J. Autoimmun., 23, 1, 10.1016/j.jaut.2004.05.001 Hu, 2004, Analysis of regulatory CD8 T cells in Qa-1-deficient mice, Nat. Immunol., 5, 516, 10.1038/ni1063 Najafian, 2003, Regulatory functions of CD8+CD28- T cells in an autoimmune disease model, J. Clin. Invest., 112, 1037, 10.1172/JCI17935 Zozulya, 2008, The role of CD8 suppressors versus destructors in autoimmune central nervous system inflammation, Hum. Immunol., 69, 797, 10.1016/j.humimm.2008.07.014 Sun, 2001, Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice, J. Immunol., 166, 7579, 10.4049/jimmunol.166.12.7579 Ford, 2005, Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis, Eur. J. Immunol., 35, 76, 10.1002/eji.200425660 Friese, 2008, Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis, Nat. Med., 14, 1227, 10.1038/nm.1881 Ji, 2010, Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs, Nat. Immunol., 11, 628, 10.1038/ni.1888 Na, 2008, Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system, Brain, 131, 2353, 10.1093/brain/awn148 Saxena, 2008, Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes, J. Immunol., 181, 1617, 10.4049/jimmunol.181.3.1617 Abdul-Majid, 2003, Comparing the pathogenesis of experimental autoimmune encephalomyelitis in CD4-/- and CD8-/- DBA/1 mice defines qualitative roles of different T cell subsets, J. Neuroimmunol., 141, 10, 10.1016/S0165-5728(03)00210-8 Kim, 2011, Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells, Semin. Immunol., 23, 446, 10.1016/j.smim.2011.06.001 Jiang, 2009, How the immune system achieves self-nonself discrimination during adaptive immunity, Adv. Immunol., 102, 95, 10.1016/S0065-2776(09)01202-4 York, 2010, Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis, J. Autoimmun., 35, 33, 10.1016/j.jaut.2010.01.003 Perchellet, 2004, CD8+ T cells maintain tolerance to myelin basic protein by ‘epitope theft’, Nat. Immunol., 5, 606, 10.1038/ni1073 Cao, 2006, Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes, Eur. J. Immunol., 36, 207, 10.1002/eji.200535211 Ji, 2013, MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8(+) T cells, Nat. Immunol., 14, 254, 10.1038/ni.2513