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Immunological Basis for the Development of Tissue Inflammation and Organ-Specific Autoimmunity in Animal Models of Multiple Sclerosis

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Book cover Molecular Basis of Multiple Sclerosis

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 51))

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) that has shaped our understanding of autoimmune tissue inflammation in the central nervous system (CNS). Major therapeutic approaches to MS have been first validated in EAE. Nevertheless, EAE in all its modifications is not able to recapitulate the full range of clinical and histopathogenic aspects of MS. Furthermore, autoimmune reactions in EAE-prone rodent strains and MS patients may differ in terms of the relative involvement of various subsets of immune cells. However, the role of specific molecules that play a role in skewing the immune response towards pathogenic autoreactivity is very similar in mice and humans. Thus, in this chapter, we will focus on the identification of a novel subset of inflammatory T cells, called Th17 cells, in EAE and their interplay with other immune cells including protective regulatory T cells (T-regs). It is likely that the discovery of Th17 cells and their relationship with T-regs will change our understanding of organ-specific autoimmune diseases in the years to come.

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References

  • Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793

    PubMed  CAS  Google Scholar 

  • Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007a) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949

    PubMed  CAS  Google Scholar 

  • Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007b) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8:639–646

    PubMed  CAS  Google Scholar 

  • Allegretta M, Nicklas JA, Sriram S, Albertini RJ (1990) T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 247:718–721

    PubMed  CAS  Google Scholar 

  • Aloisi F, Ria F, Columba-Cabezas S, Hess H, Penna G, Adorini L (1999) Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. Eur J Immunol 29:2705–2714

    PubMed  CAS  Google Scholar 

  • Antov A, Yang L, Vig M, Baltimore D, Van Parijs L (2003) Essential role for STAT5 signaling in CD25+ CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol 171:3435–3441

    PubMed  CAS  Google Scholar 

  • Archelos JJ, Storch MK, Hartung HP (2000) The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol 47:694–706

    PubMed  CAS  Google Scholar 

  • Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14:275–281

    PubMed  CAS  PubMed Central  Google Scholar 

  • Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8:1380–1389

    PubMed  CAS  Google Scholar 

  • Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schroder R, Deckert M, Schmidt S, Ravid R, Rajewsky K (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 192:393–404

    PubMed  CAS  PubMed Central  Google Scholar 

  • Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CC, Oksenberg JR (1999) B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 163:5133–5144

    PubMed  CAS  Google Scholar 

  • Baron JL, Madri JA, Ruddle NH, Hashim G, Janeway CA, Jr. (1993) Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 177:57–68

    PubMed  CAS  Google Scholar 

  • Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7:929–936

    PubMed  CAS  Google Scholar 

  • Becher B, Durell BG, Noelle RJ (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21

    PubMed  CAS  Google Scholar 

  • Ben-Nun A, Wekerle H, Cohen IR (1981) The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 11:195–199

    PubMed  CAS  Google Scholar 

  • Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M (2003) Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 349:139–145

    PubMed  CAS  Google Scholar 

  • Bettelli E, Baeten D, Jager A, Sobel RA, Kuchroo VK (2006a) Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J Clin Invest 116:2393–2402

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006b) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    PubMed  CAS  Google Scholar 

  • Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175

    PubMed  CAS  Google Scholar 

  • Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187:129–134

    PubMed  CAS  PubMed Central  Google Scholar 

  • Burns J, Bartholomew B, Lobo S (1999) Isolation of myelin basic protein-specific T cells predominantly from the memory T cell compartment in multiple sclerosis. Ann Neurol 45:33–39

    PubMed  CAS  Google Scholar 

  • Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Bussow K, Sommer N, Hemmer B (2005) Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115:1352–1360

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chang H, Hanawa H, Liu H, Yoshida T, Hayashi M, Watanabe R, Abe S, Toba K, Yoshida K, Elnaggar R, Minagawa S, Okura Y, Kato K, Kodama M, Maruyama H, Miyazaki J, Aizawa Y (2006) Hydrodynamic-based delivery of an interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats. J Immunol 177:3635–3643

    PubMed  CAS  Google Scholar 

  • Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56:2936–2946

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173:68–78

    PubMed  CAS  Google Scholar 

  • Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature 450:566–569

    PubMed  CAS  Google Scholar 

  • Colombo M, Dono M, Gazzola P, Roncella S, Valetto A, Chiorazzi N, Mancardi GL, Ferrarini M (2000) Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol 164:2782–2789

    PubMed  CAS  Google Scholar 

  • Constant S, Sant’Angelo D, Pasqualini T, Taylor T, Levin D, Flavell R, Bottomly K (1995a) Peptide and protein antigens require distinct antigen-presenting cell subsets for the priming of CD4+ T cells. J Immunol 154:4915–4923

    PubMed  CAS  Google Scholar 

  • Constant S, Schweitzer N, West J, Ranney P, Bottomly K (1995b) B lymphocytes can be competent antigen-presenting cells for priming CD4+ T cells to protein antigens in vivo. J Immunol 155:3734–3741

    PubMed  CAS  Google Scholar 

  • Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204:1757–1764

    PubMed  CAS  PubMed Central  Google Scholar 

  • Cottrell DA, Kremenchutzky M, Rice GP, Hader W, Baskerville J, Ebers GC (1999a) The natural history of multiple sclerosis: a geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis. Brain 122(Pt 4):641–647

    PubMed  Google Scholar 

  • Cottrell DA, Kremenchutzky M, Rice GP, Koopman WJ, Hader W, Baskerville J, Ebers GC (1999b) The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 122(Pt 4):625–639

    PubMed  Google Scholar 

  • Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748

    PubMed  CAS  Google Scholar 

  • Dai Y, Carayanniotis KA, Eliades P, Lymberi P, Shepherd P, Kong Y, Carayanniotis G (1999) Enhancing or suppressive effects of antibodies on processing of a pathogenic T cell epitope in thyroglobulin. J Immunol 162:6987–6992

    PubMed  CAS  Google Scholar 

  • Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S (2000) Interferon gamma eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J Exp Med 192:117–122

    PubMed  CAS  PubMed Central  Google Scholar 

  • de Graaf KL, Barth S, Herrmann MM, Storch MK, Wiesmuller KH, Weissert R (2008) Characterization of the encephalitogenic immune response in a model of multiple sclerosis. Eur J Immunol 38:299–308

    PubMed  CAS  Google Scholar 

  • Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265

    PubMed  CAS  PubMed Central  Google Scholar 

  • Dijkstra CD, De Groot CJ, Huitinga I (1992) The role of macrophages in demyelination. J Neuroimmunol 40:183–188

    PubMed  CAS  Google Scholar 

  • Du J, Huang C, Zhou B, Ziegler SF (2008) Isoform-Specific Inhibition of ROR{alpha}-Mediated Transcriptional Activation by Human FOXP3. J Immunol 180:4785–4792

    PubMed  CAS  Google Scholar 

  • Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463

    PubMed  CAS  Google Scholar 

  • Ebers GC, Koopman WJ, Hader W, Sadovnick AD, Kremenchutzky M, Mandalfino P, Wingerchuk DM, Baskerville J, Rice GP (2000) The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis. Brain 123(Pt 3):641–649

    PubMed  Google Scholar 

  • Endoh M, Tabira T, Kunishita T (1986) Antibodies to proteolipid apoprotein in chronic relapsing experimental allergic encephalomyelitis. J Neurol Sci 73:31–38

    PubMed  CAS  Google Scholar 

  • Epstein MM, Di Rosa F, Jankovic D, Sher A, Matzinger P (1995) Successful T cell priming in B cell-deficient mice. J Exp Med 182:915–922

    PubMed  CAS  Google Scholar 

  • Eynon EE, Parker DC (1992) Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 175:131–138

    PubMed  CAS  Google Scholar 

  • Farago B, Magyari L, Safrany E, Csongei V, Jaromi L, Horvatovich K, Sipeky C, Maasz A, Radics J, Gyetvai A, Szekanecz Z, Czirjak L, Melegh B (2008) Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis. Ann Rheum Dis 67:248–250

    PubMed  CAS  Google Scholar 

  • Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156:5–7

    PubMed  CAS  Google Scholar 

  • Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–950

    PubMed  CAS  Google Scholar 

  • Flugel A, Berkowicz T, Ritter T, Labeur M, Jenne DE, Li Z, Ellwart JW, Willem M, Lassmann H, Wekerle H (2001) Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14:547–560

    PubMed  CAS  Google Scholar 

  • Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341

    PubMed  CAS  Google Scholar 

  • Ford ML, Evavold BD (2005) Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol 35:76–85

    PubMed  CAS  Google Scholar 

  • Fuchs EJ, Matzinger P (1992) B cells turn off virgin but not memory T cells. Science 258:1156–1159

    PubMed  CAS  Google Scholar 

  • Gardinier MV, Amiguet P, Linington C, Matthieu JM (1992) Myelin/oligodendrocyte glycoprotein is a unique member of the immunoglobulin superfamily. J Neurosci Res 33:177–187

    PubMed  CAS  Google Scholar 

  • Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH (1998) The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 16:495–521

    PubMed  CAS  Google Scholar 

  • Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T cell differentiation. Nature 445:771–775

    PubMed  CAS  Google Scholar 

  • Genain CP, Nguyen MH, Letvin NL, Pearl R, Davis RL, Adelman M, Lees MB, Linington C, Hauser SL (1995) Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J Clin Invest 96:2966–2974

    PubMed  CAS  PubMed Central  Google Scholar 

  • Glimcher LH (2001) Lineage commitment in lymphocytes: controlling the immune response. J Clin Invest 108:s25–s30

    PubMed  CAS  Google Scholar 

  • Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971

    PubMed  Google Scholar 

  • Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334

    PubMed  CAS  Google Scholar 

  • Grundke-Iqbal I, Raine CS, Johnson AB, Brosnan CF, Bornstein MB (1981) Experimental allergic encephalomyelitis. Characterization of serum factors causing demyelination and swelling of myelin. J Neurol Sci 50:63–79

    PubMed  CAS  Google Scholar 

  • Gutcher I, Urich E, Wolter K, Prinz M, Becher B (2006) Interleukin 18-independent engagement of interleukin 18 receptor-alpha is required for autoimmune inflammation. Nat Immunol 7:946–953

    PubMed  CAS  Google Scholar 

  • Happ MP, Heber-Katz E (1988) Differences in the repertoire of the Lewis rat T cell response to self and non-self myelin basic proteins. J Exp Med 167:502–513

    PubMed  CAS  Google Scholar 

  • Hayglass KT, Naides SJ, Scott CF, Jr., Benacerraf B, Sy MS (1986) T cell development in B cell-deficient mice. IV. The role of B cells as antigen-presenting cells in vivo. J Immunol 136:823–829

    PubMed  CAS  Google Scholar 

  • Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292

    PubMed  CAS  Google Scholar 

  • Hjelmstrom P, Juedes AE, Fjell J, Ruddle NH (1998) B cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J Immunol 161:4480–4483

    PubMed  CAS  Google Scholar 

  • Hori S, Haury M, Coutinho A, Demengeot J (2002) Specificity requirements for selection and effector functions of CD25+ 4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci U S A 99:8213–8218

    PubMed  CAS  PubMed Central  Google Scholar 

  • Howell MD, Winters ST, Olee T, Powell HC, Carlo DJ, Brostoff SW (1989) Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. Science 246:668–670

    PubMed  CAS  Google Scholar 

  • Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J (2001) A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 194:669–676

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P, Maruoka M, Mao W, Foster J, Kelley RF, Pan G, Gurney AL, de Vos AM, Starovasnik MA (2001) IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J 20:5332–5341

    PubMed  CAS  PubMed Central  Google Scholar 

  • Illes Z, Safrany E, Peterfalvi A, Magyari L, Farago B, Pozsonyi E, Rozsa C, Komoly S, Melegh B (2008) 3´YTR C2370A allele of the IL-23 receptor gene is associated with relapsing-remitting multiple sclerosis. Neurosci Lett 431:36–38

    PubMed  CAS  Google Scholar 

  • Issazadeh S, Mustafa M, Ljungdahl A, Hojeberg B, Dagerlind A, Elde R, Olsson T (1995) Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J Neurosci Res 40:579–590

    PubMed  CAS  Google Scholar 

  • Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The Orphan Nuclear Receptor RORgammat Directs the Differentiation Program of Proinflammatory IL-17(+) T Helper Cells. Cell 126:1121–1133

    PubMed  CAS  Google Scholar 

  • Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP, Iwakura Y, Maloy KJ, Powrie F (2008) Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28:559–570

    PubMed  CAS  PubMed Central  Google Scholar 

  • Janeway CA, Jr., Ron J, Katz ME (1987) The B cell is the initiating antigen-presenting cell in peripheral lymph nodes. J Immunol 138:1051–1055

    PubMed  Google Scholar 

  • Jung S, Schluesener HJ, Toyka KV, Hartung HP (1993) Modulation of EAE by vaccination with T cell receptor peptides: V beta 8 T cell receptor peptide-specific CD4+ lymphocytes lack direct immunoregulatory activity. J Neuroimmunol 45:15–22

    PubMed  CAS  Google Scholar 

  • Kabat EA, Wolf A, Bezer AE (1946) Rapid Production of Acute Disseminated Encephalomyelitis in Rhesus Monkeys by Injection of Brain Tissue With Adjuvants. Science 104:362–363

    Google Scholar 

  • Kappos L, Traboulsee A, Constantinescu C, Eralinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B, Uitdehaag B, Li D (2006) Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 67:944–953

    PubMed  CAS  Google Scholar 

  • Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A (2005) Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med 201:1805–1814

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human T(H)17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175

    PubMed  CAS  Google Scholar 

  • Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, Locksley RM, Haynes L, Randall TD, Cooper AM (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8:369–377

    PubMed  CAS  Google Scholar 

  • Kim KJ, Rollwagen F, Asofsky R, Lefkovits I (1984) The abnormal function of T cells in chronically anti-mu-treated mice with no mature B lymphocytes. Eur J Immunol 14:476–482

    PubMed  CAS  Google Scholar 

  • Kleinschek MA, Owyang AM, Joyce-Shaikh B, Langrish CL, Chen Y, Gorman DM, Blumenschein WM, McClanahan T, Brombacher F, Hurst SD, Kastelein RA, Cua DJ (2007) IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 204:161–170

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kohm AP, Carpentier PA, Anger HA, Miller SD (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 169:4712–4716

    PubMed  CAS  Google Scholar 

  • Kojima K, Berger T, Lassmann H, Hinze-Selch D, Zhang Y, Gehrmann J, Reske K, Wekerle H, Linington C (1994) Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia. J Exp Med 180:817–829

    PubMed  CAS  Google Scholar 

  • Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476

    PubMed  CAS  Google Scholar 

  • Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573

    PubMed  CAS  Google Scholar 

  • Kono DH, Urban JL, Horvath SJ, Ando DG, Saavedra RA, Hood L (1988) Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice. J Exp Med 168:213–227

    PubMed  CAS  Google Scholar 

  • Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007a) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487

    PubMed  CAS  PubMed Central  Google Scholar 

  • Korn T, Oukka M, Kuchroo V, Bettelli E (2007b) Th17 cells: Effector T cells with inflammatory properties. Semin Immunol 19:362–371

    PubMed  CAS  PubMed Central  Google Scholar 

  • Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Backstrom BT, Sobel RA, Wucherpfennig KW, Strom TB, Oukka M, Kuchroo VK (2007c) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 13:423–431

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kremenchutzky M, Cottrell D, Rice G, Hader W, Baskerville J, Koopman W, Ebers GC (1999) The natural history of multiple sclerosis: a geographically based study. 7. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation. Brain 122 (Pt 10):1941–1950

    PubMed  Google Scholar 

  • Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC (2006) The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 129:584–594

    PubMed  CAS  Google Scholar 

  • Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, Heppner FL, Renauld JC, Becher B (2007) IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol 179:8098–8104

    PubMed  CAS  Google Scholar 

  • Krishnamoorthy G, Lassmann H, Wekerle H, Holz A (2006) Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest 116:2385–2392

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kuchroo VK, Martin CA, Greer JM, Ju ST, Sobel RA, Dorf ME (1993) Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J Immunol 151:4371–4382

    PubMed  CAS  Google Scholar 

  • Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB (2002) T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu Rev Immunol 20:101–123

    PubMed  CAS  Google Scholar 

  • Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, Polman CH, Miller DH, Montalban X, Barkhof F, Bauer L, Dahms S, Lindberg R, Kappos L, Sandbrink R (2007) Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 356:371–378

    PubMed  CAS  Google Scholar 

  • Kurt-Jones EA, Liano D, HayGlass KA, Benacerraf B, Sy MS, Abbas AK (1988) The role of antigen-presenting B cells in T cell priming in vivo. Studies of B cell-deficient mice. J Immunol 140:3773–3778

    PubMed  CAS  Google Scholar 

  • Lafaille JJ, Keere FV, Hsu AL, Baron JL, Haas W, Raine CS, Tonegawa S (1997) Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J Exp Med 186:307–312

    PubMed  CAS  PubMed Central  Google Scholar 

  • Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lanzavecchia A (1990) Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol 8:773–793

    PubMed  CAS  Google Scholar 

  • Lassila O, Vainio O, Matzinger P (1988) Can B cells turn on virgin T cells? Nature 334:253–255

    PubMed  CAS  Google Scholar 

  • Lassmann H, Brunner C, Bradl M, Linington C (1988) Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol 75:566–576

    PubMed  CAS  Google Scholar 

  • Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea J J (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    PubMed  CAS  Google Scholar 

  • Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G (1993) Determinant spreading and the dynamics of the autoimmune T cell repertoire. Immunol Today 14:203–208

    PubMed  CAS  Google Scholar 

  • Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181:381–386

    PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146

    PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T Cell-Produced Transforming Growth Factor-beta1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation. Immunity 26:579–591

    PubMed  CAS  Google Scholar 

  • Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279

    PubMed  CAS  PubMed Central  Google Scholar 

  • Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130:443–454

    PubMed  CAS  PubMed Central  Google Scholar 

  • Litzenburger T, Fassler R, Bauer J, Lassmann H, Linington C, Wekerle H, Iglesias A (1998) B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice. J Exp Med 188:169–180

    PubMed  CAS  PubMed Central  Google Scholar 

  • Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, Kane JP, Saccone S, Worthington J, Bruce I, Kwok PY, Menter A, Krueger J, Barton A, Saccone NL, Bowcock AM (2008) A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease Loci. PLoS Genet 4:e1000041

    Google Scholar 

  • Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508

    PubMed  CAS  Google Scholar 

  • Lohr J, Knoechel B, Wang JJ, Villarino AV, Abbas AK (2006) Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J Exp Med 203:2785–2791

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    PubMed  CAS  Google Scholar 

  • Lyons JA, San M, Happ MP, Cross AH (1999) B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur J Immunol 29:3432–3439

    PubMed  CAS  Google Scholar 

  • Lyons JA, Ramsbottom MJ, Cross AH (2002) Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein. Eur J Immunol 32:1905–1913

    PubMed  CAS  Google Scholar 

  • Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9:641–649

    PubMed  CAS  PubMed Central  Google Scholar 

  • Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    PubMed  CAS  Google Scholar 

  • Mann MK, Maresz K, Shriver LP, Tan Y, Dittel BN (2007) B cell regulation of CD4+ CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J Immunol 178:3447–3456

    PubMed  CAS  Google Scholar 

  • Martin R, McFarland HF (1995) Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 32:121–182

    PubMed  CAS  Google Scholar 

  • Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, Al-Hayani A, Davies SN, Rasband MN, Olsson T, Moldenhauer A, Velhin S, Hohlfeld R, Meinl E, Linington C (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204:2363–2372

    PubMed  CAS  PubMed Central  Google Scholar 

  • McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    PubMed  CAS  Google Scholar 

  • McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8:1390–1397

    PubMed  CAS  Google Scholar 

  • McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11:335–339

    PubMed  CAS  Google Scholar 

  • McRae BL, Kennedy MK, Tan LJ, Dal Canto MC, Picha KS, Miller SD (1992) Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J Neuroimmunol 38:229–240

    PubMed  CAS  Google Scholar 

  • McRae BL, Vanderlugt CL, Dal Canto MC, Miller SD (1995) Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J Exp Med 182:75–85

    PubMed  CAS  Google Scholar 

  • Mendel I, Kerlero de Rosbo N, Ben-Nun A (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 25:1951–1959

    PubMed  CAS  Google Scholar 

  • Mendel Kerlero de Rosbo N, Ben-Nun A (1996) Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse V beta gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V beta b and T cell receptor V beta a H-2b mice. Eur J Immunol 26:2470–2479

    PubMed  CAS  Google Scholar 

  • Miller SD, Vanderlugt CL, Begolka WS, Pao W, Yauch RL, Neville KL, Katz-Levy Y, Carrizosa A, Kim BS (1997) Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat Med 3:1133–1136

    PubMed  CAS  Google Scholar 

  • Moore GR, Raine CS (1988) Immunogold localization and analysis of IgG during immune-mediated demyelination. Lab Invest 59:641–648

    PubMed  CAS  Google Scholar 

  • Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    PubMed  CAS  Google Scholar 

  • Morris SC, Lees A, Finkelman FD (1994) In vivo activation of naive T cells by antigen-presenting B cells. J Immunol 152:3777–3785

    PubMed  CAS  Google Scholar 

  • Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    PubMed  CAS  Google Scholar 

  • Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260

    PubMed  CAS  Google Scholar 

  • Myers KJ, Sprent J, Dougherty JP, Ron Y (1992) Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis. J Neuroimmunol 41:1–8

    PubMed  CAS  Google Scholar 

  • Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483

    PubMed  CAS  Google Scholar 

  • Oksenberg JR, Panzara MA, Begovich AB, Mitchell D, Erlich HA, Murray RS, Shimonkevitz R, Sherritt M, Rothbard J, Bernard CC et al (1993) Selection for T cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 362:68–70

    PubMed  CAS  Google Scholar 

  • Oliver AR, Lyon GM, Ruddle NH (2003) Rat and human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice. J Immunol 171:462–468

    PubMed  CAS  Google Scholar 

  • Olsson T (1992) Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma. J Neuroimmunol 40:211–218

    PubMed  CAS  Google Scholar 

  • Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725

    PubMed  CAS  Google Scholar 

  • Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Connor KC, Hafler DA, Sobel RA, Robinson WH, Steinman L (2007) Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448:474–479

    PubMed  CAS  Google Scholar 

  • Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467

    PubMed  CAS  PubMed Central  Google Scholar 

  • Owens GP, Kraus H, Burgoon MP, Smith-Jensen T, Devlin ME, Gilden DH (1998) Restricted use of VH4 germline segments in an acute multiple sclerosis brain. Ann Neurol 43:236–243

    PubMed  CAS  Google Scholar 

  • Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    PubMed  CAS  PubMed Central  Google Scholar 

  • Phillips JA, Romball CG, Hobbs MV, Ernst DN, Shultz L, Weigle WO (1996) CD4+ T cell activation and tolerance induction in B cell knockout mice. J Exp Med 183:1339–1344

    PubMed  CAS  Google Scholar 

  • Piddlesden S, Lassmann H, Laffafian I, Morgan BP, Linington C (1991) Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation. Clin Exp Immunol 83:245–250

    PubMed  CAS  PubMed Central  Google Scholar 

  • Piddlesden SJ, Lassmann H, Zimprich F, Morgan BP, Linington C (1993) The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol 143:555–564

    PubMed  CAS  PubMed Central  Google Scholar 

  • Pierce SK, Morris JF, Grusby MJ, Kaumaya P, van Buskirk A, Srinivasan M, Crump B, Smolenski LA (1988) Antigen-presenting function of B lymphocytes. Immunol Rev 106:149–180

    PubMed  CAS  Google Scholar 

  • Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, Rodriguez M (2004) Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 56:303–306

    PubMed  Google Scholar 

  • Probert L, Eugster HP, Akassoglou K, Bauer J, Frei K, Lassmann H, Fontana A (2000) TNFR1 signalling is critical for the development of demyelination and the limitation of T cell responses during immune-mediated CNS disease. Brain 123(Pt 10):2005–2019

    PubMed  Google Scholar 

  • Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J (1998) Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102:1045–1050

    PubMed  CAS  PubMed Central  Google Scholar 

  • Reddy J, Illes Z, Zhang X, Encinas J, Pyrdol J, Nicholson L, Sobel RA, Wucherpfennig KW, Kuchroo VK (2004) Myelin proteolipid protein-specific CD4+ CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 101:15434–15439

    PubMed  CAS  PubMed Central  Google Scholar 

  • Rivers TM, Schwentker FF (1935) Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J Exp Med 61:689–702

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ron Y, De Baetselier P, Gordon J, Feldman M, Segal S (1981) Defective induction of antigen-reactive proliferating T cells in B cell-deprived mice. Eur J Immunol 11:964–968

    PubMed  CAS  Google Scholar 

  • Ronchese F, Hausmann B (1993) B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes. J Exp Med 177:679–690

    PubMed  CAS  Google Scholar 

  • Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR, Jr., Muller W, Rudensky AY (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28:546–558

    PubMed  CAS  Google Scholar 

  • Russell WL, Russell LB, Gower JS (1959) Exceptional Inheritance of a Sex-Linked Gene in the Mouse Explained on the Basis That the X/O Sex-Chromosome Constitution Is Female. Proc Natl Acad Sci U S A 45:554–560

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    PubMed  CAS  Google Scholar 

  • Sato W, Aranami T, Yamamura T (2007) Cutting edge: Human Th17 cells are identified as bearing CCR2+ CCR5- phenotype. J Immunol 178:7525–7529

    PubMed  CAS  Google Scholar 

  • Schluesener HJ, Sobel RA, Linington C, Weiner HL (1987) A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 139:4016–4021

    PubMed  CAS  Google Scholar 

  • Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276:37672–37679

    PubMed  CAS  Google Scholar 

  • Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K (1993) Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11:729–766

    PubMed  CAS  Google Scholar 

  • Simitsek PD, Campbell DG, Lanzavecchia A, Fairweather N, Watts C (1995) Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J Exp Med 181:1957–1963

    PubMed  CAS  Google Scholar 

  • Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747

    PubMed  CAS  Google Scholar 

  • Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H (1998) Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol 43:465–471

    PubMed  CAS  Google Scholar 

  • Stuart G, Krikorian KS (1928) The neuro-paralytic accidents of anti-rabies treatment. Ann Trop Med Parasitol 22:327–377

    Google Scholar 

  • Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, O’Shea JJ, Hennighausen L, Ernst M, Hunter CA (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7:937–945

    PubMed  CAS  Google Scholar 

  • Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJ, O’Shea JJ, Hunter CA (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8:1363–1371

    PubMed  CAS  Google Scholar 

  • Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, Raine CS (2001) Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 166:7579–7587

    PubMed  CAS  Google Scholar 

  • Svensson L, Abdul-Majid KB, Bauer J, Lassmann H, Harris RA, Holmdahl R (2002) A comparative analysis of B cell-mediated myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis pathogenesis in B cell-deficient mice reveals an effect on demyelination. Eur J Immunol 32:1939–1946

    PubMed  CAS  Google Scholar 

  • Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669

    PubMed  CAS  Google Scholar 

  • Tabira T, Endoh M (1985) Humoral immune responses to myelin basic protein, cerebroside and ganglioside in chronic relapsing experimental allergic encephalomyelitis of the guinea pig. J Neurol Sci 67:201–212

    PubMed  CAS  Google Scholar 

  • Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7:83–92

    PubMed  CAS  PubMed Central  Google Scholar 

  • Thompson EJ, Kaufmann P, Shortman RC, Rudge P, McDonald WI (1979) Oligoclonal immunoglobulins and plasma cells in spinal fluid of patients with multiple sclerosis. Br Med J 1:16–17

    PubMed  CAS  PubMed Central  Google Scholar 

  • Traugott U, Lebon P (1988a) Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann Neurol 24:243–251

    PubMed  CAS  Google Scholar 

  • Traugott U, Lebon P (1988b) Interferon-gamma and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions. J Neurol Sci 84:257–264

    PubMed  CAS  Google Scholar 

  • Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D (2007) Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449:361–365

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tripp CS, Gately MK, Hakimi J, Ling P, Unanue ER (1994) Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-gamma. J Immunol 152:1883–1887

    CAS  Google Scholar 

  • Tuohy VK, Lu Z, Sobel RA, Laursen RA, Lees MB (1989) Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J Immunol 142:1523–1527

    PubMed  CAS  Google Scholar 

  • Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172:146–155

    PubMed  CAS  PubMed Central  Google Scholar 

  • Van der Goes A, Kortekaas M, Hoekstra K, Dijkstra CD, Amor S (1999) The role of anti-myelin (auto)-antibodies in the phagocytosis of myelin by macrophages. J Neuroimmunol 101:61–67

    PubMed  CAS  Google Scholar 

  • van der Veen RC, Sobel RA, Lees MB (1986) Chronic experimental allergic encephalomyelitis and antibody responses in rabbits immunized with bovine proteolipid apoprotein. J Neuroimmunol 11:321–333

    PubMed  CAS  Google Scholar 

  • Vandenbark AA, Chou YK, Whitham R, Mass M, Buenafe A, Liefeld D, Kavanagh D, Cooper S, Hashim GA, Offner H (1996) Treatment of multiple sclerosis with T cell receptor peptides: results of a double-blind pilot trial. Nat Med 2:1109–1115

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006a) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006b) Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7:1151–1156

    PubMed  CAS  Google Scholar 

  • Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9:650–657

    PubMed  CAS  Google Scholar 

  • Wang LY, Fujinami RS (1997) Enhancement of EAE and induction of autoantibodies to T cell epitopes in mice infected with a recombinant vaccinia virus encoding myelin proteolipid protein. J Neuroimmunol 75:75–83

    PubMed  CAS  Google Scholar 

  • Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC (1989a) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112(Pt 1):133–146

    PubMed  Google Scholar 

  • Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC (1989b) The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 112(Pt 6):1419–1428

    PubMed  Google Scholar 

  • Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC (1991a) The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome. Brain 114(Pt 2):1045–1056

    PubMed  Google Scholar 

  • Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC (1991b) The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials. Brain 114(Pt 2):1057–1067

    PubMed  Google Scholar 

  • Wekerle H, Kojima K, Lannes-Vieira J, Lassmann H, Linington C (1994) Animal models. Ann Neurol 36(Suppl):S47–S53

    PubMed  CAS  Google Scholar 

  • Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20

    PubMed  CAS  Google Scholar 

  • Willenborg DO, Prowse SJ (1983) Immunoglobulin-deficient rats fail to develop experimental allergic encephalomyelitis. J Neuroimmunol 5:99–109

    PubMed  CAS  Google Scholar 

  • Willenborg DO, Sjollema P, Danta G (1986) Immunoglobulin deficient rats as donors and recipients of effector cells of allergic encephalomyelitis. J Neuroimmunol 11:93–103

    PubMed  CAS  Google Scholar 

  • Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA (1996) IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157:3223–3227

    PubMed  CAS  Google Scholar 

  • Willenborg DO, Staykova M, Fordham S, O’Brien N, Linares D (2007) The contribution of nitric oxide and interferon gamma to the regulation of the neuro-inflammation in experimental autoimmune encephalomyelitis. J Neuroimmunol 191:16–25

    PubMed  CAS  Google Scholar 

  • Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284

    PubMed  CAS  Google Scholar 

  • Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957

    PubMed  CAS  Google Scholar 

  • Wolf SD, Dittel BN, Hardardottir F, Janeway CA, Jr. (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 184:2271–2278

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yan J, Harvey BP, Gee RJ, Shlomchik MJ, Mamula MJ (2006) B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol 177:4481–4487

    PubMed  CAS  Google Scholar 

  • Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    PubMed  CAS  Google Scholar 

  • Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA (2008a) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352

    Google Scholar 

  • Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008b) T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORalpha RORgamma. Immunity 28:29–39

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811–821

    PubMed  CAS  Google Scholar 

  • Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356:63–66

    PubMed  CAS  Google Scholar 

  • Zamvil SS, Mitchell DJ, Moore AC, Kitamura K, Steinman L, Rothbard JB (1986) T cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324:258–260

    PubMed  CAS  Google Scholar 

  • Zamvil SS, Mitchell DJ, Powell MB, Sakai K, Rothbard JB, Steinman L (1988) Multiple discrete encephalitogenic epitopes of the autoantigen myelin basic protein include a determinant for I-E class II-restricted T cells. J Exp Med 168:1181–1186

    PubMed  CAS  Google Scholar 

  • Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8:579–621

    PubMed  CAS  Google Scholar 

  • Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA (2007) Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27:647–659

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA (1994) Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 179:973–984

    PubMed  CAS  Google Scholar 

  • Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, Kamoun M, Rostami A (2003) Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol 170:2153–2160

    PubMed  CAS  Google Scholar 

  • Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445:648–651

    PubMed  CAS  Google Scholar 

  • Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14:282–289

    PubMed  CAS  Google Scholar 

  • Zhou L, Ivanov, II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974

    PubMed  CAS  Google Scholar 

  • Zhou L, Lopes JE, Chong MM, Ivanov, II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240

    PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgement

TK and MM are supported by the Deutsche Forschungsgemeinschaft (KO 2964/2–1 and MI 1221/1–1).

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Authors and Affiliations

  1. Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany

    Thomas Korn

  2. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Meike Mitsdoerffer & Vijay K. Kuchroo

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  1. Thomas Korn
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  2. Meike Mitsdoerffer
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  3. Vijay K. Kuchroo
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Correspondence to Thomas Korn or Vijay K. Kuchroo .

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Editors and Affiliations

  1. Institut für Neuroimmunologie und, Klinische Multiple-Sklerose-Forschung, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, Hamburg, 20251, Germany

    Roland Martin

  2. , Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, Innsbruck, 6020, Austria

    Andreas Lutterotti

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Korn, T., Mitsdoerffer, M., Kuchroo, V.K. (2009). Immunological Basis for the Development of Tissue Inflammation and Organ-Specific Autoimmunity in Animal Models of Multiple Sclerosis. In: Martin, R., Lutterotti, A. (eds) Molecular Basis of Multiple Sclerosis. Results and Problems in Cell Differentiation, vol 51. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_2008_17

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