Abstract
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. It is believed to be an autoimmune disease arising from a breakdown of immune tolerance in T cells specific for myelin antigens. The heterogeneity in clinical signs and pathology observed in MS patients suggests a complex pathogenesis in which the specificity of the pathogenic T cells and the tolerance mechanisms that are compromised vary among individual patients. In this review, we summarize some of the features of the diverse immune pathology observed in MS and the animal models used to study this disease. We then describe the current state of knowledge regarding the expression of the major myelin protein antigens believed to be targeted in MS and the mechanisms of immune tolerance that operate on T cells that recognize these antigens.
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Whitaker JN, Mitchell GW: Clinical features of Multiple Sclerosis: in Raine CS, McFarland H, Tourtellotte WW (eds). Multiple Sclerosis: Clinical and Pathogenetic Basis, London, Chapman and Hall, 1997 pp. 3–19.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717.
Lassmann H, Raine CS, Antel J, Prineas JW: Immunopathology of multiple sclerosis: report on aninternational meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunoll 1998;86:213–217.
Hemmer B, Cepok S, Nessler S, Sommer N: Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol 2002;15:227–231.
Zamvil SS, Steinman L: The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 1990;8:579–621.
Martin R, McFarland HF: Immunology of multiple sclerosis and experimental allergic encephalomyelitis, in Raine CS, McFarland HF, Tourte Ilotte WW (eds): Multiple Sclerosis: Clinical and Pathogenetic Basis, London, Chapman and Hall, 1997 pp. 221–242.
Raine C: The Lesion in Multiple Sclerosis and Chronic Relapsing Experimental Allergic Encephalomyelitis: A Structural COmparison: in Raine CS, McFarland HF, Tourtellotte WW (eds) Multiple Sclerosis: Clinical and Pathogenetic Basis. London, Chapman and Hall, 1997 pp. 243–286.
Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C: T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 2001; 36:220–234.
Maatta JA, Kaldman MS, Sakoda S, Salmi AA, Hinkkanen AE: Encephalitogenicity of myelin-associated oligodendrocytic basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase for BALB/c and SJL mice. Immunol 1998;95:383–388.
Kaye JF, Kerlerod R, Mendel I, Flechter S, Hoffman M, Yust I, et al.: The central nervous system-specific myclin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS). J Neuroimmunol 2000;102:189–198.
Holz A, Bielekova B, Martin R, Oldstone MB: Myelin-associated oligodendrocytic basic protein: identification of an encephalitogenic epitope and association with multiple sclerosis. J Immunol 2000;164:1103–1109.
Dharmasaroja P: Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis. J Neurol Sci 2003;206:7–16.
de Rosbo NK, Ben Nun A: T-cell responses to myelin antigens in multiple sclerosis; relevance of the predominant autoimmune reactivity to myelin oligodendrocyte glycoprotein. J Autoimmun 1998;11:287–299.
Genain CP, Cannella B, Hauser SL, Raine CS: Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999;5:170–175.
Warren KG, Catz I, Steinman L: Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B-cell epitope and a model of its features. Proc Natl Acad Sci USA 1995;92:11061–11065.
Sun JB, Olsson T, Wang WZ, Xiao BG, Kostulas V, Fredrikson S, et al.: Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls. Eur J Immunol 1991;21:1461–1468.
Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T cells. Annu Rev Immunol 2003;21:139–176.
Hammerling GJ, Schonrich G, Momburg F, Auphan N, Malissen M, Malissen B, et al.: Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue-specific expression of a foreign MHC class 1 antigen. Immunol Rev 1991;122:47–67.
de Visser KE, Cordaro TA, Kessels HW, Tirion FH, Schumacher TN, Krusibeek AM: Low-avidity self-specific T cells display a pronounced expansion defect that can be overcome by altered peptide ligands. J Immunol 2001;167:3818–3828.
Bouneaud C, Kourilsky P, Bousso P: Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 2000;13:829–840.
Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC: Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 1995;3:407–415.
Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, et al.: Ablation of “tolerance” and induction of diabetes by virus infection in vivral antigen transgenic mice. Cell 1991;65:305–317.
Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM: Transgenic mice that expressa myelinbasic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 1993;72:551–560.
Miller JF, Kurts C, Allison J, Kosaka H, Carbone F, Heath WR: Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens. Immunol Rev 1998;165:267–277.
Van Parijs L, Abbas AK: Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 1998;280:243–248.
Shevach EM: Regulatory T cells in autoimmunity. Annu Rev Immunol 2000:18:423–449.
Walker LS, Abbas AK: The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2002;2:11–19.
Williams KC, Hickey WF: Traffic of hematogenous cells through the central nervous system. Curr Top Microbiol Immunol 1995;202:221–245.
Wekerle H, Linnington H, Lassmann H, Meyermann R: Cellular immune reactivity within the CNS. Trends in Neurosci 1986;9:271–277.
Hickey WF, Hsu BL, Kimura H: T-lymphocyte entry into the central nervous system. J Neurosci Res 1991; 28:254–260.
Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J: In-Situ Tolerance within the CNS as a Mechanism for Preventing Autoimmunity. Journal of Experimental Medicine. 2000. Ref Type: In Press
Hickey WF: Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 1999;11:125–137.
Derbinski J, Schulte A, Kyewski B, Klein L: Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001; 2:1032–1039.
Voskuhl RR: Myclin protein expression in lymphoid tissues: implications for peripheral tolerance. Immunol Rev 1998;164:81–92.
Nave KA, Milner RJ: Proteolipid proteins: structure and genetic expression in normal and myclin-deficient mutant mice. Crit Rev Neurobiol 1989;5:65–91.
Agrawal HC, Burton RM, Fishman MA, Mitchell RF, Prensky AL: Partial characterization of a new myelin protein component. J Neurochem 1972;19:2083–2089.
Nave KA, Lai C, Bloom FE, Milner RJ: Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central ner vous system myelin. Proc Natl Acad Sci USA 1987;84:5665–5669.
Timsit S, Sinoway MP, Levy L, Allinquant B Stempak J, Staugaitis SM, et al.: The DM20 protein of myelin: intracellular and surface expression patterns in transfectants. J Neurochem 1992;58:1936–1942.
Dickinson PJ, Fanarraga ML, Griffiths IR, Barrie JM, Kyriakides E, Montague P: Oligodendrocyte progenitors in the embryonic spinal cord express DM-20. Neuropathol Appl. Neurobiol 1996;22:188–198.
Sporkel O, Uschkureit T, Bussow H, Stoffel W: Oligodendrocytes expressing exclusively the DM20 isoform of the proteolipid protein gene: myelination and development. Glia 2002;37:19–30
Agrawal HC, Agrawal D: Proteolipid protein and DM-20 are synthesized by Schwann cells, present in myelin membrane, but they are not fatty acylated. Neurochem Res 1991;16:855–858.
Lemke G: in Zach W. Hall (ed): An Introduction to Molecular Neurobiology. Sunderland, Massachusetts, Sinauer Associates, Inc., 1992 pp 281–309.
Garbern JY, Cambi F, Tang XM, Sima AA, Vallat JM, Bosch EP, et al.: Proteolipid protein is necessary in peripheral as well as central myelin. Neuron 1997;19: 205–218.
Pribyl TM, Campagnoni CW, Kampf K, Kashima T, Handley VW, McMahon J, et al.: Expression of the myelin proteolipid protein gene in the human fetal thymus. J Neuroimmunol 1996;67:125–130.
Campagnoni CW, Garbay B, Micevych P, Pribyl T, Kampf K, Handley VW, et al.: DM 20 mRNA spliceproduct of the myelin proteolipid protein gene is expressed in the murine heart. J Neurosci Res 1992;33:148–155.
Anderson AC, Nicholson LB, Legge KL, Turchin V, Zaghouani H, Kuchroo VK: High frequency of autore-active myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J Exp Med 2000;191:761–770.
Klein L, Klugmann M, Nave KA, Tuohy VK, Kyewski B, Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat Med 2000;6:56–61.
Bongarzone ER, Campagnoni CW, Kampf K, Jacobs EC, Handley VW, Schonmann V, et al. Identification of a new exon in the myelin proteo-lipid protein gene encoding novel protein isoforms that are restricted to the somata of oligodendrocytes and neurons. J Neurosci 1999;19:8349–8357.
Tuohy VK, Lu Z, Sobel RA, Laursen RA, Lees MB: Identification of an encephalitogenic, determinant of myelin proteolipid protein for SJL mice. J Immunol 1989;142:1523–1527.
Legge KL, Min B, Potter NT, Zaghouani H: Presentation of a T cell receptor antagonist peptide by immunoglobulins ablates activation of T cells by asynthetic peptide or proteins requiring endocytic processing. J Exp Med 1997;185:1043–1053.
Waldner H, Whitters MJ, Sobel RA, Collins M, Kuchroo VK: Fulmmant spontaneous autoimmunity of the central nervous system in myelin proteolipid protein specific T cell receptor transgenic mice. Proc Natl Acad Sci USA 2000.
Linnington C, Webb M, Woodhams PL: A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody. J Neuroimmunol 1984;6:387–396.
Kroepfl JF, Vijse LR, Charron AJ, Linington C, Gardinier MV: Investigation of myelin/oligodendrocyte glycoprotein membrane topology. J Neurochem 1996; 67:2219–2222.
Bruno R, Sabater L, Sospedra M, Ferrer-Francesch X, Escudero D, Martinez-Caceres E, et al: Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus. Eur J Immunol 2002;32:2737–2747.
Pagany M, Jagodic M, Schubart A, Pham-Dinh D, Bachelin C, van Evercooren AB, et al.: Myelin oligodendrocyte glycoprotein is expressed in the peripheral nervous system of rodents and primates. Neurosci Lett 2003;350:165–168.
Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK: Myelin oligodendrocyte glycoprote inspecific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med 2003;197: 1073–1081.
Delarsse C, Daubas P, Mars LT, Vizler C, Litzenburger T, Iglesias A et al: Myelin/oligodendrocyte glycoprotein-deficienc (MOG-deficient) mice revial lack of immune tolerance to MOG in wild-type mice. J Clin Invest 2003;112:544–553.
Schluesener HJ, Sobel RA, Linington C, Weiner HL: A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 1987;139:4016–4021.
Linington C, Bradl M, Lassmann H, Brunner C, Vass K: Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 1988;130:443–454.
Genain CP, Nguyen MH, Letvin NL, Pearl R, Davis RL, Adelman M, et al.: Antibody facilitation of multiplesclerosis-like lesions in a nonhuman primate. J Clin Invest 1995;96:2966–2974.
Linington C, Berger T, Perry L, Weerth S, Hinze Selch D, Zhang Y, et al.: T cells specific for the myelin oligodendrocyte glycoprotein mediate and unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 1993;23:1364–1372.
Stefferl A, Brehm U, Storch M, Lambracht-Washington D, Bourquin C, Wonigeit K, et al.: Myelin oligodendrocyte glycoprotein induces experimentalautoimmune encephalomyelitis in the “resistant” Brown Norway rat: disease susceptibility is determined by MHC and MHC-linked effects on the B cell response. J Immunol 1999; 163:40–49.
Brehm U, Piddlesden SJ, Gardinier MV, Lington C: Epitopes pecificity of demyelinating monoclonal autoan-tibodies directed against the human myelin oligodendrocyle glycoprotein (MOG). J Neuroimmunol 1999; 97:9–15.
von Budingen HC, Hauser SL, Fuhrmann A, Nabavi CB, Lee JI, Genain CP: Molecular characterization of anti-body specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination. Proc Natl Acad Sci U S A 2002;99:8207–8212.
Hjelmstrom P, Juedes AE, Fjell J, Ruddle NH: B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodend rocyte glycoprotein sensitization. J Immunol 1998;161:4480–4483.
Lyons JA, San M, Happ MP, Cross AH: B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short ence phalitogenic peptide. Eur J Immunol 1999;29:3432–3439.
Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A: IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 1998;28:2178–2187.
Oliver AR, Lyon GM, Ruddle NH: Ratand human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice. J Immunol 2003;171:462–468.
Litzenburger T, Bluthmann H, Morales P, Pham-Dinh D, Dautigny A, Wekerle H, et al: Development of myelin oligodend rocyte glycoprotein auto reactive transgenic B lymphocytes: recepto rediting in vivo after encounter of a self-antigen distinct from myelin oligodend rocyte glycoprotein. J Immunol 2000;165:5360–5366.
Litzenburger T, Fassler R, Bauer J, Lassmann H, Linington C, Wekerle H, et al: B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice. J Exp Med 1998; 188:169–180.
Bouroquin C, Schubart A, Tobollik S, Mather I, Ogg S, Liblau R, Linington C: Selective unresponsiveness to conformational B cell epitopes of the myelin oligodendrocytegly coprotein in H-2b mice. J Immunol 2003;171: 455–461.
Campagnoni AT, Pribyl TM, Campagnoni CW, Kampf K, Amur Umarjee S, Landry CF, et al.: Structure and developmental regulation of Goll i-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem 1993;268:4930–4938.
Pribyl TM, Campagnoni CW, Kampf K, Kashima T, Handley VW, McMahon J, et al.: The human myelin basic protein gene is included within a 179-kilobase transcription unit: expression in the immune and central nervous systems. Proc Natl Acad Sci USA 1993; 90:10695–10699.
Givogri MI, Bongarzone ER, Campagnoni AT: New insights on the biology of myelin basic protein gene: the neural-immune connection. J Neurosci Res 2000; 59:153–159.
Lemke G: Unwrapping the genes of myelin. Neuron 1988;1:535–543.
Privat A, Jacque C, Bourre JM, Dupouey P, Baumann N: Absence of the major dense line in myelin of the mutant mouse “shiverer”. Neurosci Lett 1979;12: 107–112.
Omlin FX, Webster HD, Palkovits CG, Cohen SR: Immunocytochemical localization of basic protein in major dense lineregions of central and peripheral myelin. J Cell Biol 1982;95:242–248.
Martini R, Mohajeri MH, Kasper S, Giese KP, Schachner M: Mice doubly deficient in the genes for PO and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J. Neurosci 1995;15:4488–4495.
Campagnoni AT, Skoff RP: The pathobiology of myelin mutants reveal novel biological functions of the MBP and PLP genes. Brain Pathol 2001;11:74–91.
de Ferra F, Engh H, Hudson L, Kamholz J, Puckett C, Molineaux S, et al.: Alternative splicing accounts for the four forms of myelin basic protein. Cell 1985; 43:721–727.
Newman S, Kitamura K, Campagnoni AT: Identification of a cDNA coding for a fifth form of myelin basic protein in mouse. Proc Natl Acad Sci USA 1987;84: 886–890.
Kitamura K, Newman SL, Campagnoni CW, Verdi JM, Mohandas T, Handley VW, et al: Expression of a novel transcript of the myelin basic protein gene. J Neurochem 1990;54:2032–2041.
Mathisen PM, Pease S, Garvey J, Hood L, Readhead C: Identification of an embryonic iso form of myelin basic protein that is expressed widely in the mouse embryo. Proc Natl Acad Sci USA 1993;90:10125–10129.
Barbarese E, Carson JH, Braun PE: Accumulation of the four myelin basic proteins in mouse brain during development. J Neurochem 1978;31:779–782.
Liu H, MacKenzie-Graham AJ, Palaszynski K, Liva S, Voskuhl RR: “Classic” myelin basic proteins are expressed in lymphoid tissue macrophages. J Neuro-immunol 2001:116:83–93.
Grima B, Zelenika D, Pessac B: A novel transcriptoverlapping the myelin basic protein gene. J Neurochem 1992;59:2318–2323.
Zelenika D, Grima B, Pessac B: A new family of transcripts of the myelin basic protein gene: expression in brain and in immune system. J Neurochem 1993;60: 1574–1577.
Landry CF, Ellison JA, Pribyl TM, Campagnoni C, Kampf K, Campagnoni AT: Myelin basic protein gene expression in neurons: developmental and regional changes in protein targeling within neuronal nuclei, cell bodies, and processes. J Neurosci 1996;16: 2452–2462.
Pribyl TM, Campagnoni CW, Kampf K, Ellison JA, Landry CF, Kashima T, et al: Expression of the myelin basic protein gene locus in neurons and oligodendrocytes in the human fetal central nervous system. J Comp Neurol 1996;374:342–353.
Landry CF, Ellison J, Skinner E, Campagnoni AT: Golli-MBP proteins mark the earliest stages of fiber extension and terminal arboration in the mouse peripheral nervous system. J Neurosci Res 1997;50:265–271.
Feng JM, Fermandes AO, Campagnoni AT: Golli-myelin basic proteins delineate the nerve distribution of lymphoid organs. J Neuroimmunol 2002:123:1–8.
Fritz RB, Kalvakolanu I: Thymic expression of the golli-myelin basic protein gene in the SJL/J mouse. J Neuroimmunol 1995;57:93–99.
Marty MC, Alliot F, Ratin J, Fritz R, Trisler D, Pessac B: The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors. Proc Natl Acad Sci U S A 2002;99:8856–8861.
Pitchekian-Halabi H, Campagnoni CW, Skinner E, Kampf K, Campagnoni AT, Voskuhl RR: Strain-related differences in the ability of T lymphocytes to recognize proteins encoded by the golli-myelin basic protein gene. J Neuroimmunol 1996;68:121–129.
Maverakis E, Mendoza R, Southwood, S, Raja-Gabaglia C, Abromson-Leeman S, Campagnoni AT, et al.: Immunogenicity of self antigens is unrelated to MHC-binding affinity: T-cell determinant structure of Golli-MBP in the BALB/c mouse. J Autoimmun 2000;15:315–322.
Tranquill LR, Skinner E, Campagnoni C, Vergelli M, Hemmer B, Muraro P, et al.: Human T lymphocytes specific for the immunodominant 83–99 epitope of myelin basic protein: recognition of golli MB P HOG 7. J Neurosci Res 1996;45:820–828.
Wucherpfennig KW, Zhang J, Witek C, Matsui M, Modabber Y, Ota K, et al.: Clonal expansion and persistence of human T cells specific foranimmunodominantmyelin basic protein peptide. J Immunol 1994;152:5581–5592.
Goebels N, Hofstetter H, Schmidt S, Brunner C, Wekerle H, Hohlfeld R: Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence. Brain 2000;123 Pt 3:508–518.
Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, et al.: Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 1994;179:279–290.
Vergelli M, Kalbus M, Rojo SC, Hemmer B, Kalbacher H, Tranquill L, et al.: T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR 15 haplotype: peptide binding, immunodominance and effector functions of T cells. J Neuroimmunol 1997;77:195–203.
Manoury B, Mazzeo D, Fugger L, Viner N, Porsford M, Streeter H, et al.: Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 2002;3:169–174.
Krogsgaard M, Wucherpfennig KW, Canella B, Hansen BE, Svejgaard A, Pyrdol J, et al.: Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J Exp Med 2000;191:1395–1412.
Kimura M, Inoko H, Katsuki M, Ando A, Sato T, Hirose T, et al.: Molecular genetic analysis of myelin-deficient mice: shiverer mutant mice show deletion in gene(s) coding for myelin basic protein. J Neurochem 1985; 44:692–696.
Roach A, Takahashi N, Pravtcheva D, Ruddle F, Hood L: Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell 1985;42:149–155.
Molineaux SM, Engh H, de Ferra F, Hudson L, Lazzarini RA: Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation. Proc Natl Acad Sci USA 1986;83:7542–7546.
Kirschner DA, Ganser AL: Compact myelin exists in the absence of basic protein in the shiverermutant mouse. Nature 1980;283:207–210.
Roach A, Takahashi N, Pravtcheva D, Ruddle F, Hood L: Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell 1985;42:149–155.
Harrington CJ, Paez A, Hunkapiller T, Mannikko V, Brabb T, Ahearn M, et al.: Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 1998;8:571–580.
Targoni OS, Lehmann PV: Endogenous myelin basic protein inactivates the high avidity T cell repertoire. J Exp Med 1998;187:2055–2063.
Yoshizawa I, Bronson R, Dorf ME, Abromson-Leeman S: T-cell responses to myelin basic protein in normal and MBP-deficientmice. J Neuroimmunol 1998;84:131–138.
Fairchild PJ, Wildgoose R, Atherton E, Webb S, Wraith DC: Anautoanti genic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction. Int Immunol 1993;5:1151–1158.
Mason K, Denney DW, Jr., McConnel HM: Kinetics of the reaction of a myelin basic protein peptide with soluble IAu. Biochemistry 1995;34:14874–14878.
Lee C, Liang MN, Tate KM, Rabinowitz JD, Beeson C, Jones PP, et al.: Evidence that the autoimmune antigen myelin basic protein (MBP) Ac 1–9 binds towards one end of the major histocompatibility complex (MHC) cleft. J Exp Med 1998;187:1505–1516.
He XL, Radu C, Sidney J, Sette A, Ward ES, Garcia KC: Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au. Immunity 2002;17:83–94.
Loftus C, Huseby E, Gopaul P, Beeson C, Goverman J: Highly cross-reactive T cell responses to myelin basic protein epitopes reveal a nonpredictable form of TCR degeneracy. J Immunol 1999;162:6451–6457.
Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S: High incidence of spontaneous autoimmune encephalomyelitis in immunodeficientanti-myelin basic protein T cell receptor transgenic mice. Cell 1994;78:399–408.
Brabb T, Goldrath AW, von Dassow P, Paez A, Liggitt HD, Goverman J: Toggers of autoimmune disease in a murine T-cell receptor transgenic model for multiple sclerosis. J Immunol 1997;159:497–507.
Goverman J: Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein. Immunol Rev 1999;169:147–159.
Keere Vde, Tonegawa S: CD4(+) T cells prevent spontaneous experimentalauto immune encephalomyelitis in anti-myelin basic protein T cell receptor transgenic mice. J Exp Med 1998;188:1875–1882.
Olivares-Villagomez D, Wang Y, Lafaille JJ: Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J Exp Med 1998;188:1883–1894.
Olivares-Villagomez D, Wensky AK, Wang Y, Lafaille JJ: Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis. J Immunol 2000;164:5499–5507.
Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ: Regulatory T cells inspontaneous autoimmune encephalomyelitis. Immunol Rev 2001;182:122–134.
Hori S, Haury M, Coutinho A, Demengeot J: 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 USA 2002;99:8213–8218.
Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J: In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J Exp Med 2000;192:871–880.
Huseby ES, Sather B, Huseby PG, Goverman J: Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity 2001;14:471–481.
Seamons A, Sutton J, Bai D, Baird E, Bonn N, Kafsack BFC et al.: Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity. J Exp Med 2003;197:1391–1397.
Fairchild PJ, Pope H, Wraith DC: The nature of cryptic epitopes within the self-antigen myelin basic protein. Int Immunol 1996;8:1035–1043.
Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, et al.: 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 2000; 192:393–404.
Jacobsen M, Cepok S, Quak E, Happel M, Gaber R, Ziegler A, et al.: Oligoclonalex pansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 2002;125:538–550.
Jurewicz A, Biddison WE, Antel JP: MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes. J Immunol 1998;160:3056–3059.
Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, et al.: Myelin antigen-specific CD8+ T cells are encepha litogenic and produce severe disease in C57BL/6 mice. J Immunol 2001;166:7579–7587.
Huseby ES, Ohlen C, Goverman J: Cuttingedge: myelin basic protein-specific cytotoxic T cell tolerance is maintained in vivo by asingle dominant epitope in H-2k mice. J Immunol 1999;163:1115–1118.
Huseby ES, Liggitt D, Brabb T, Schrabel B, Ohlen C, Goverman J: A pathogenic role formyelin-specific CD8+ T cells in a model for Multiple Sclerosis. J Exp Med 2001;194:669–676.
Feng JM, Givogri IM, Bongarzone ER, Campagnoni C, Jacobs E, Handley VW, et al.: Thymocytes express the golliproducts of the myelin basic protein gene and levels of expression are stage dependent. J Immunol 2000;165:5443–5450.
Schulz R, Mellor AL: Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment. J Exp Med 1996;184:1573–1578.
Jhaver KG, Chandler P, Simpson E, Mellor AL: Thymocyte antigens do not induce tolerance in the CD4+ T cell compartment. J Immunol 1999;163:4851–4858.
Pircher H, Muller KP, Kyewski BA, Hengartner H: Thymocytes can tolerize thymocytes by clonal deletion in vitro. Int Immunol 1992;4:1065–1069.
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Seamons, A., Perchellet, A. & Goverman, J. Immune tolerance to myelin proteins. Immunol Res 28, 201–221 (2003). https://doi.org/10.1385/IR:28:3:201
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DOI: https://doi.org/10.1385/IR:28:3:201