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Molecular Basis of Multiple Sclerosis pp 149–172Cite as

Antigen Processing and Presentation in Multiple Sclerosis

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

Abstract

CD4+ T cells play a central role in the pathogenesis of multiple sclerosis (MS). Generation, activation and effector function of these cells crucially depends on their interaction with MHC II-peptide complexes displayed by antigen presenting cells (APC). Processing and presentation of self antigens by different APC therefore influences the disease course at all stages. Selection by thymic APC leads to the generation of autoreactive T cells, which can be activated by peripheral APC. Reactivation by central nervous system APC leads to the initiation of the inflammatory response resulting in demyelination. In this review we will focus on how MHC class II antigenic epitopes are created by different APC from the thymus, the periphery and from the brain, and will discuss the relevance of the balance between creation and destruction of such epitopes in the context of MS. A solid understanding of these processes offers the possibility for designing future therapeutic strategies.

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References

  • Anderson AC, Nicholson LB, Legge KL, Turchin V, Zaghouani H, Kuchroo VK (2000) High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J Exp Med 191:761–770. doi:10.1084/jem.191.5.761

    PubMed Central  PubMed  CAS  Google Scholar 

  • Anderton SM, Wraith DC (2002) Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol 2:487–498

    PubMed  CAS  Google Scholar 

  • Anderton SM, Viner NJ, Matharu P, Lowrey PA, Wraith DC (2002) Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat Immunol 3:175–181

    PubMed  CAS  Google Scholar 

  • Antel J, Bar-Or A (2006) Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment. J Neuroimmunol 180:3–8

    PubMed  CAS  Google Scholar 

  • Bailey SL, Schreiner B, McMahon EJ, Miller SD (2007) CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 8:172–180

    PubMed  CAS  Google Scholar 

  • Baxter AG (2007) The origin and application of experimental autoimmune encephalomyelitis. Nat Rev Immunol 7:904–912

    PubMed  CAS  Google Scholar 

  • Beck H, Schwarz G, Schroter CJ, Deeg M, Baier D, Stevanovic S, Weber E, Driessen C, Kalbacher H (2001) Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro. Eur J Immunol 31:3726–3736

    PubMed  CAS  Google Scholar 

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

    PubMed Central  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 

  • Brahms H, Raymackers J, Union A, de Keyser F, Meheus L, Luhrmann R (2000) The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J Biol Chem 275:17122–17129

    PubMed  CAS  Google Scholar 

  • Bruno R, Sabater L, Sospedra M, Ferrer-Francesch X, Escudero D, Martinez-Caceres E, Pujol-Borrell R (2002) Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus. Eur J Immunol 32:2737–2747

    PubMed  CAS  Google Scholar 

  • Burster T, Beck A, Tolosa E, Marin-Esteban V, Rotzschke O, Falk K, Lautwein A, Reich M, Brandenburg J, Schwarz G, Wiendl H, Melms A, Lehmann R, Stevanovic S, Kalbacher H, Driessen C (2004) Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J Immunol 172:5495–5503

    PubMed  CAS  Google Scholar 

  • Burster T, Beck A, Tolosa E, Schnorrer P, Weissert R, Reich M, Kraus M, Kalbacher H, Haring HU, Weber E, Overkleeft H, Driessen C (2005) Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells. J Immunol 175:5940–5949

    PubMed  CAS  Google Scholar 

  • Burster T, Beck A, Poeschel S, Oren A, Baechle D, Reich M, Roetzschke O, Falk K, Boehm BO, Youssef S, Kalbacher H, Overkleeft H, Tolosa E, Driessen C (2007a) Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro. Immunology 121:82–93

    PubMed Central  PubMed  CAS  Google Scholar 

  • Burster T, Marin-Esteban V, Boehm BO, Dunn S, Rotzschke O, Falk K, Weber E, Verhelst SH, Kalbacher H, Driessen C (2007b) Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. Biochem Pharmacol 74:1514–1523

    PubMed  CAS  Google Scholar 

  • Cao L, Goodin R, Wood D, Moscarello MA, Whitaker JN (1999) Rapid release and unusual stability of immunodominant peptide 45–89 from citrullinated myelin basic protein. Biochemistry 38:6157–6163

    PubMed  CAS  Google Scholar 

  • Castellino F, Zappacosta F, Coligan JE, Germain RN (1998) Large protein fragments as substrates for endocytic antigen capture by MHC class II molecules. J Immunol 161:4048–4057

    PubMed  CAS  Google Scholar 

  • Correale J, McMillan M, McCarthy K, Le T, Weiner LP (1995) Isolation and characterization of autoreactive proteolipid protein-peptide specific T-cell clones from multiple sclerosis patients. Neurology 45:1370–1378

    PubMed  CAS  Google Scholar 

  • Corthay A, Backlund J, Holmdahl R (2001) Role of glycopeptide-specific T cells in collagen-induced arthritis: an example how post-translational modification of proteins may be involved in autoimmune disease. Ann Med 33:456–465

    PubMed  CAS  Google Scholar 

  • Costantino CM, Hang HC, Kent SC, Hafler DA, Ploegh HL (2008) Lysosomal cysteine and aspartic proteases are heterogeneously expressed and act redundantly to initiate human invariant chain degradation. J Immunol 180:2876–2885

    PubMed  CAS  Google Scholar 

  • Cross AH, Trotter JL, Lyons J (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 112:1–14

    PubMed  CAS  Google Scholar 

  • Day MJ, Tse AG, Puklavec M, Simmonds SJ, Mason DW (1992) Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats. J Exp Med 175:655–659

    PubMed  CAS  Google Scholar 

  • de Vos AF, van Meurs M, Brok HP, Boven LA, Hintzen RQ, van der Valk P, Ravid R, Rensing S, Boon L, t Hart BA, Laman JD (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169:5415–5423

    PubMed  CAS  Google Scholar 

  • Delarasse C, Daubas P, Mars LT, Vizler C, Litzenburger T, Iglesias A, Bauer J, Della Gaspera B, Schubart A, Decker L, Dimitri D, Roussel G, Dierich A, Amor S, Dautigny A, Liblau R, Pham-Dinh D (2003) Myelin/oligodendrocyte glycoprotein-deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice. J Clin Invest 112:544–553

    PubMed Central  PubMed  CAS  Google Scholar 

  • Denzin LK, Cresswell P (1995) HLA-DM induces CLIP dissociation from MHC class II alpha beta dimers and facilitates peptide loading. Cell 82:155–165

    PubMed  CAS  Google Scholar 

  • Denzin LK, Sant’Angelo DB, Hammond C, Surman MJ, Cresswell P (1997) Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science 278:106–109

    PubMed  CAS  Google Scholar 

  • Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039

    PubMed  CAS  Google Scholar 

  • Doyle HA, Mamula MJ (2005) Posttranslational modifications of self-antigens. Ann N Y Acad Sci 1050:1–9

    PubMed  CAS  Google Scholar 

  • Eggleton P, Haigh R, Winyard PG (2008) Consequence of neo-antigenicity of the ‘altered self’. Rheumatology (Oxford) 47:567–571

    CAS  Google Scholar 

  • Fazilleau N, Delarasse C, Sweenie CH, Anderton SM, Fillatreau S, Lemonnier FA, Pham-Dinh D, Kanellopoulos JM (2006) Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)-specific T cell repertoires in MOG-expressing mice. Eur J Immunol 36:533–543

    PubMed  CAS  Google Scholar 

  • Fiebiger E, Meraner P, Weber E, Fang IF, Stingl G, Ploegh H, Maurer D (2001) Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells. J Exp Med 193:881–892

    PubMed Central  PubMed  CAS  Google Scholar 

  • Fissolo N, Kraus M, Reich M, Ayturan M, Overkleeft H, Driessen C, Weissert R (2008) Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation. Eur J Immunol 38:2401–2411

    PubMed  CAS  Google Scholar 

  • Fridkis-Hareli M, Teitelbaum D, Gurevich E, Pecht I, Brautbar C, Kwon OJ, Brenner T, Arnon R, Sela M (1994) Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells–specificity and promiscuity. Proc Natl Acad Sci USA 91:4872–4876

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R (2003) Thymic generation and regeneration. Immunol Rev 195:28–50

    PubMed  CAS  Google Scholar 

  • Goebels N, Hofstetter H, Schmidt S, Brunner C, Wekerle H, Hohlfeld R (2000) Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence. Brain 123(Pt 3):508–518

    PubMed  Google Scholar 

  • Goodnow CC, Sprent J, de St F, Groth B, Vinuesa CG (2005) Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590–597

    PubMed  CAS  Google Scholar 

  • Greer JM, Pender MP (2008) Myelin proteolipid protein: an effective autoantigen and target of autoimmunity in multiple sclerosis. J Autoimmun 31:281–287

    PubMed  CAS  Google Scholar 

  • Greer JM, Csurhes PA, Muller DM, Pender MP (2008) Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J Immunol 180:6402–6410

    PubMed  CAS  Google Scholar 

  • Gregersen JW, Kranc KR, Ke X, Svendsen P, Madsen LS, Thomsen AR, Cardon LR, Bell JI, Fugger L (2006) Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443:574–577

    PubMed  CAS  Google Scholar 

  • Gresser O, Weber E, Hellwig A, Riese S, Regnier-Vigouroux A (2001) Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S. Eur J Immunol 31:1813–1824

    PubMed  CAS  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 

  • Harauz G, Musse AA (2007) A tale of two citrullines–structural and functional aspects of myelin basic protein deimination in health and disease. Neurochem Res 32:137–158

    PubMed  CAS  Google Scholar 

  • Hatterer E, Touret M, Belin MF, Honnorat J, Nataf S (2008) Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS ONE 3:e3321

    PubMed Central  PubMed  Google Scholar 

  • Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–152

    PubMed  CAS  Google Scholar 

  • Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E (2003) Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 171:538–541

    PubMed  CAS  Google Scholar 

  • Hogquist KA, Baldwin TA, Jameson SC (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5:772–782

    PubMed  CAS  Google Scholar 

  • Holmes S, Siebold C, Jones EY, Friese MA, Fugger L, Bell J (2005) Multiple sclerosis: MHC associations and therapeutic implications. Expert Rev Mol Med 7:1–17

    PubMed  Google Scholar 

  • Honey K, Rudensky AY (2003) Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 3:472–482

    PubMed  CAS  Google Scholar 

  • Honey K, Nakagawa T, Peters C, Rudensky A (2002) Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J Exp Med 195:1349–1358

    PubMed Central  PubMed  CAS  Google Scholar 

  • Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C (2001) T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36:220–234

    PubMed  CAS  Google Scholar 

  • Kappos L, Comi G, Panitch H, Oger J, Antel J, Conlon P, Steinman L (2000) Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The altered peptide ligand in relapsing MS study group. Nat Med 6:1176–1182

    PubMed  CAS  Google Scholar 

  • Karman J, Ling C, Sandor M, Fabry Z (2004) Initiation of immune responses in brain is promoted by local dendritic cells. J Immunol 173:2353–2361

    PubMed  CAS  Google Scholar 

  • Kerlero de Rosbo N, Hoffman M, Mendel I, Yust I, Kaye J, Bakimer R, Flechter S, Abramsky O, Milo R, Karni A, Ben-Nun A (1997) Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions. Eur J Immunol 27:3059–3069

    PubMed  CAS  Google Scholar 

  • Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R, Moscarello MA (2003) Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis. Mol Cell Proteomics 2:453–462

    PubMed  CAS  Google Scholar 

  • Kirberg J, Berns A, von Boehmer H (1997) Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J Exp Med 186:1269–1275

    PubMed Central  PubMed  CAS  Google Scholar 

  • Klein L, Klugmann M, Nave KA, Tuohy VK, Kyewski B (2000) Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat Med 6:56–61

    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 Central  PubMed  CAS  Google Scholar 

  • Krogsgaard M, Wucherpfennig KW, Cannella B, Hansen BE, Svejgaard A, Pyrdol J, Ditzel H, Raine C, Engberg J, Fugger L (2000) 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 191:1395–1412

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606

    PubMed  CAS  Google Scholar 

  • Laatsch RH, Kies MW, Gordon S, Alvord EC Jr (1962) The encephalomyelitic activity of myelin isolated by ultracentrifugation. J Exp Med 115:77–88

    Google Scholar 

  • Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA, Tiislar M, Ferretti V, Tienari PJ, Sadovnick AD, Peltonen L, Ebers GC, Hudson TJ (2005) A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 37:1108–1112

    PubMed  CAS  Google Scholar 

  • Lindert RB, Haase CG, Brehm U, Linington C, Wekerle H, Hohlfeld R (1999) Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein. Brain 122(Pt 11):2089–2100

    PubMed  Google Scholar 

  • Linington C, Berger T, Perry L, Weerth S, Hinze-Selch D, Zhang Y, Lu HC, Lassmann H, Wekerle H (1993) T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 23:1364–1372

    PubMed  CAS  Google Scholar 

  • Lippolis JD, White FM, Marto JA, Luckey CJ, Bullock TN, Shabanowitz J, Hunt DF, Engelhard VH (2002) Analysis of MHC class II antigen processing by quantitation of peptides that constitute nested sets. J Immunol 169:5089–5097

    PubMed  Google Scholar 

  • Madsen LS, Andersson EC, Jansson L, Krogsgaard M, Andersen CB, Engberg J, Strominger JL, Svejgaard A, Hjorth JP, Holmdahl R, Wucherpfennig KW, Fugger L (1999) A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat Genet 23:343–347

    PubMed  CAS  Google Scholar 

  • Maehr R, Mintern JD, Herman AE, Lennon-Dumenil AM, Mathis D, Benoist C, Ploegh HL (2005) Cathepsin L is essential for onset of autoimmune diabetes in NOD mice. J Clin Invest 115:2934–2943

    PubMed Central  PubMed  CAS  Google Scholar 

  • Mamula MJ, Gee RJ, Elliott JI, Sette A, Southwood S, Jones PJ, Blier PR (1999) Isoaspartyl post-translational modification triggers autoimmune responses to self-proteins. J Biol Chem 274:22321–22327

    PubMed  CAS  Google Scholar 

  • Manoury B, Hewitt EW, Morrice N, Dando PM, Barrett AJ, Watts C (1998) An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396:695–699

    PubMed  CAS  Google Scholar 

  • Manoury B, Mazzeo D, Fugger L, Viner N, Ponsford M, Streeter H, Mazza G, Wraith DC, Watts C (2002) Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 3:169–174

    PubMed  CAS  Google Scholar 

  • Martin R, Jaraquemada D, Flerlage M, Richert J, Whitaker J, Long EO, McFarlin DE, McFarland HF (1990) Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J Immunol 145:540–548

    PubMed  CAS  Google Scholar 

  • Marty MC, Alliot F, Rutin J, Fritz R, Trisler D, Pessac B (2002) The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors. Proc Natl Acad Sci USA 99:8856–8861

    PubMed Central  PubMed  CAS  Google Scholar 

  • Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA (2007) Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res 85:2006–2016

    PubMed  CAS  Google Scholar 

  • McDevitt HO, Perry R, Steinman LA (1987) Monoclonal anti-Ia antibody therapy in animal models of autoimmune disease. Ciba Found Symp 129:184–193

    PubMed  CAS  Google Scholar 

  • McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919

    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, 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 

  • Meinl E, Weber F, Drexler K, Morelle C, Ott M, Saruhan-Direskeneli G, Goebels N, Ertl B, Jechart G, Giegerich G et al (1993) Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones. J Clin Invest 92:2633–2643

    PubMed Central  PubMed  CAS  Google Scholar 

  • Melms A, Luther C, Stoeckle C, Poschel S, Schroth P, Varga M, Wienhold W, Tolosa E (2006) Thymus and myasthenia gravis: antigen processing in the human thymus and the consequences for the generation of autoreactive T cells. Acta Neurol Scand 183:12–13

    CAS  Google Scholar 

  • Moss CX, Matthews SP, Lamont DJ, Watts C (2005) Asparagine deamidation perturbs antigen presentation on class II major histocompatibility complex molecules. J Biol Chem 280:18498–18503

    PubMed  CAS  Google Scholar 

  • Moss CX, Tree TI, Watts C (2007) Reconstruction of a pathway of antigen processing and class II MHC peptide capture. EMBO J 26:2137–2147

    PubMed Central  PubMed  CAS  Google Scholar 

  • Musse AA, Li Z, Ackerley CA, Bienzle D, Lei H, Poma R, Harauz G, Moscarello MA, Mastronardi FG (2008) Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Dis Model Mech 1:229–240

    PubMed Central  PubMed  CAS  Google Scholar 

  • Nakagawa T, Roth W, Wong P, Nelson A, Farr A, Deussing J, Villadangos JA, Ploegh H, Peters C, Rudensky AY (1998) Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280:450–453

    PubMed  CAS  Google Scholar 

  • Narayan K, Chou CL, Kim A, Hartman IZ, Dalai S, Khoruzhenko S, Sadegh-Nasseri S (2007) HLA-DM targets the hydrogen bond between the histidine at position beta81 and peptide to dissociate HLA-DR-peptide complexes. Nat Immunol 8:92–100

    PubMed Central  PubMed  CAS  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    PubMed  CAS  Google Scholar 

  • Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Panayi G, Chernajovsky Y (2005) Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint. Arthritis Rheum 52:3829–3838

    PubMed  CAS  Google Scholar 

  • Odoardi F, Kawakami N, Klinkert WE, Wekerle H, Flugel A (2007) Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease. Proc Natl Acad Sci USA 104:18625–18630

    PubMed Central  PubMed  CAS  Google Scholar 

  • Pelfrey CM, Trotter JL, Tranquill LR, McFarland HF (1993) Identification of a novel T cell epitope of human proteolipid protein (residues 40–60) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients. J Neuroimmunol 46:33–42

    PubMed  CAS  Google Scholar 

  • Pfender NA, Grosch S, Roussel G, Koch M, Trifilieff E, Greer JM (2008) Route of uptake of palmitoylated encephalitogenic peptides of myelin proteolipid protein by antigen-presenting cells: importance of the type of bond between lipid chain and peptide and relevance to autoimmunity. J Immunol 180:1398–1404

    PubMed  CAS  Google Scholar 

  • Pinet V, Vergelli M, Martin R, Bakke O, Long EO (1995) Antigen presentation mediated by recycling of surface HLA-DR molecules. Nature 375:603–606

    PubMed  CAS  Google Scholar 

  • Prat E, Tomaru U, Sabater L, Park DM, Granger R, Kruse N, Ohayon JM, Bettinotti MP, Martin R (2005) HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype. J Neuroimmunol 167:108–119

    PubMed  CAS  Google Scholar 

  • Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7:1356–1361

    PubMed  CAS  Google Scholar 

  • Pritzker LB, Joshi S, Gowan JJ, Harauz G, Moscarello MA (2000a) Deimination of myelin basic protein. 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D. Biochemistry 39:5374–5381

    PubMed  CAS  Google Scholar 

  • Pritzker LB, Joshi S, Harauz G, Moscarello MA (2000b) Deimination of myelin basic protein. 2. Effect of methylation of MBP on its deimination by peptidylarginine deiminase. Biochemistry 39:5382–5388

    PubMed  CAS  Google Scholar 

  • Quandt JA, Baig M, Yao K, Kawamura K, Huh J, Ludwin SK, Bian HJ, Bryant M, Quigley L, Nagy ZA, McFarland HF, Muraro PA, Martin R, Ito K (2004) Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111–129-specific humanized TCR transgenic mice. J Exp Med 200:223–234

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ristori G, Carcassi C, Lai S, Fiori P, Cacciani A, Floris L, Montesperelli C, Di Giovanni S, Buttinelli C, Contu L, Pozzilli C, Salvetti M (1997) HLA-DM polymorphisms do not associate with multiple sclerosis: an association study with analysis of myelin basic protein T cell specificity. J Neuroimmunol 77:181–184

    PubMed  CAS  Google Scholar 

  • Rudensky A, Beers C (2006) Lysosomal cysteine proteases and antigen presentation. Ernst Schering Res Found Workshop. 56:81–95

    Google Scholar 

  • Saegusa K (2002) Cathepsin S inhibitor prevents autoantigen processing and autoimmunity. J Clin Invest 110:361–369

    PubMed Central  PubMed  CAS  Google Scholar 

  • Seamons A, Perchellet A, Goverman J (2006) Endogenous myelin basic protein is presented in the periphery by both dendritic cells and resting B cells with different functional consequences. J Immunol 177:2097–2106

    PubMed  CAS  Google Scholar 

  • Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Capello E, Mancardi GL, Aloisi F (2006) Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 65:124–141

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Sospedra M, Ferrer-Francesch X, Dominguez O, Juan M, Foz-Sala M, Pujol-Borrell R (1998) Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J Immunol 161:5918–5929

    PubMed  CAS  Google Scholar 

  • Stoeckle C, Burster T, Gnau V, Driessen C, Kalbacher H, Melms A, Tolosa E (2004) Is processing regulated in patients with multiple sclerosis? Immunology 3:285–291

    Google Scholar 

  • Stoeckle C, Herrmann M, Burster T, Beck A, Weissert R, Melms A, Tolosa E (2008) Autoantigen processing in the CNS during autoimmune inflammation. J Neuroimmunol 203:226

    Google Scholar 

  • Stoeckle C, Sommandas V, Adamopoulou E, Belisle K, Schiekofer S, Melms A, Weber E, Driessen C, Boehm BO, Tolosa E, Burster T (2009) Cathepsin G is differentially expressed in primary human antigen-presenting cells. Cell Immunol 255:41–45

    PubMed  CAS  Google Scholar 

  • Sweenie CH, Mackenzie KJ, Rone-Orugboh A, Liu M, Anderton SM (2007) Distinct T cell recognition of naturally processed and cryptic epitopes within the immunodominant 35–55 region of myelin oligodendrocyte glycoprotein. J Neuroimmunol 183:7–16

    PubMed  CAS  Google Scholar 

  • Szekanecz Z, Soos L, Szabo Z, Fekete A, Kapitany A, Vegvari A, Sipka S, Szucs G, Szanto S, Lakos G (2008) Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets? Clin Rev Allergy Immunol 34:26–31

    PubMed  Google Scholar 

  • Taubert R, Schwendemann J, Kyewski B (2007) Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur J Immunol 37:838–848

    PubMed  CAS  Google Scholar 

  • Tolosa E, Li W, Yasuda Y, Wienhold W, Denzin LK, Lautwein A, Driessen C, Schnorrer P, Weber E, Stevanovic S, Kurek R, Melms A, Bromme D (2003) Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 112:517–526

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tranquill LR, Cao L, Ling NC, Kalbacher H, Martin RM, Whitaker JN (2000) Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients. Mult Scler 6:220–225

    PubMed  CAS  Google Scholar 

  • Trombetta ES, Mellman I (2005) Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol 23:975–1028

    PubMed  CAS  Google Scholar 

  • Tselios T, Apostolopoulos V, Daliani I, Deraos S, Grdadolnik S, Mavromoustakos T, Melachrinou M, Thymianou S, Probert L, Mouzaki A, Matsoukas J (2002) Antagonistic effects of human cyclic MBP(87–99) altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation. J Med Chem 45:275–283

    PubMed  CAS  Google Scholar 

  • Vanderlugt CL, Miller SD (2002) Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol 2:85–95

    PubMed  CAS  Google Scholar 

  • Vergelli M, Kalbus M, Rojo SC, Hemmer B, Kalbacher H, Tranquill L, Beck H, McFarland HF, De Mars R, Long EO, Martin R (1997a) T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR15 haplotype: peptide binding, immunodominance and effector functions of T cells. J Neuroimmunol 77:195–203

    PubMed  CAS  Google Scholar 

  • Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, Riccio P, Long EO, Martin R (1997b) HLA-DR-restricted presentation of purified myelin basic protein is independent of intracellular processing. Eur J Immunol 27:941–951

    PubMed  CAS  Google Scholar 

  • Villadangos JA, Schnorrer P (2007) Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 7:543–555

    PubMed  CAS  Google Scholar 

  • Vogt AB, Kropshofer H, Kalbacher H, Kalbus M, Rammensee HG, Coligan JE, Martin R (1994) Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from self-peptides. J Immunol 153:1665–1673

    PubMed  CAS  Google Scholar 

  • Waldner H, Whitters MJ, Sobel RA, Collins M, Kuchroo VK (2000) Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. Proc Natl Acad Sci USA 97:3412–3417

    PubMed Central  PubMed  CAS  Google Scholar 

  • Wallberg M, Bergquist J, Achour A, Breij E, Harris RA (2007) Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and encephalitogenicity. Eur J Immunol 37:1986–1995

    PubMed  Google Scholar 

  • Wallstrom E, Khademi M, Andersson M, Weissert R, Linington C, Olsson T (1998) Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15) + multiple sclerosis. Eur J Immunol 28:3329–3335

    PubMed  CAS  Google Scholar 

  • Warren KG, Catz I, Ferenczi LZ, Krantz MJ (2006) Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-. Eur J Neurol 13:887–895

    PubMed  CAS  Google Scholar 

  • Weissert R, Kuhle J, de Graaf KL, Wienhold W, Herrmann MM, Muller C, Forsthuber TG, Wiesmuller KH, Melms A (2002) High immunogenicity of intracellular myelin oligodendrocyte glycoprotein epitopes. J Immunol 169:548–556

    PubMed  CAS  Google Scholar 

  • Westley BR, May FE (1987) Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive human breast cancer cells. Nucleic Acids Res 15:3773–3786

    PubMed Central  PubMed  CAS  Google Scholar 

  • Wilson NS, El-Sukkari D, Villadangos JA (2004) Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood 103:2187–2195

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of General Neurology, Hertie Institute for Clinical Brain Research, Otfried-Mueller-Str. 27, 72076, Tuebingen, Germany

    Christina Stoeckle

  2. Center for Molecular Neurobiology Hamburg (ZMNH), Institute for Neuroimmunology and Clinical MS Research (INiMS), Falkenried 94, 20251, Hamburg, Germany

    Eva Tolosa

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  1. Christina Stoeckle
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  2. Eva Tolosa
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Correspondence to Christina Stoeckle .

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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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Stoeckle, C., Tolosa, E. (2009). Antigen Processing and Presentation in 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_2009_22

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