Skip to main content
SpringerLink
Log in

Molecular mimicry and multiple sclerosis — a possible role for degenerate T cell recognition in the induction of autoimmune responses

  • Conference paper
Advances in Research on Neurodegeneration

Part of the book series: 6th International Winter Conference on N eurodegeneration ((NEURAL SUPPL,volume 55))

Summary

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The etiology is unknown, but several lines of evidence support the hypothesis that the pathogenesis is mediated by autoreactive T lymphocytes. Molecular mimicry has been proposed as a possible mechanism for the development of an autoimmune response to myelin antigens. According to this model, an immune reaction to self antigens could be initiated by T cells that cross-react with infectious agents that “mimic” the autoantigen, i.e. they share immunologic epitopes. It was previously thought that, in order for a cross-reaction of T cells to two different antigens to occur, a substantial amino acid sequence homology between the two antigens was required. More recent studies on the basic mechanisms of T cell antigen recognition have shown that, at least for some T cell clones, antigen recognition is more “degenerate” and sequence homology is not required for crossreactivity to occur. This article reviews the relevance of these recent advances in basic T cell receptor immunology to the occurrence of autoimmunity in the central nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alberola-Ila J, Takaki S, Kerner JD, Perlmutter RM (1997) Differential signaling by lymphocyte antigen receptors. Annu Rev Immunol 15: 125–154.

    Article  PubMed  CAS  Google Scholar 

  • Barnaba V, Sinigaglia F (1997) Molecular mimicry and T cell-mediated autoimmune disease. J Exp Med 185: 1529–1531.

    Article  PubMed  CAS  Google Scholar 

  • Cannella B, Cross AH, Raine CS (1990) Upregulation and coexpression of adhesion molecules correlate with relapsing autoimmune demyelination in the central nervous system. J Exp Med 172: 1521–1524.

    Article  PubMed  CAS  Google Scholar 

  • Davies JM (1997) Molecular mimicry: can epitope mimicry induce autoimmune disease? Immunol Cell Biol 75: 113–126.

    Article  PubMed  CAS  Google Scholar 

  • Ebers GC, Sadovnick AD, Risch NJ (1995) A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 377: 150–151.

    Article  PubMed  CAS  Google Scholar 

  • Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, Armstrong H, Cousin K, Bell RB, Hader W, Paty DW, Hashimoto S, Oger J, Duquette P, Warren S, Gray T, O’Connor P, Nath A, Auty A, Metz L, Francis G, Paulseth JE, Murray TJ, Pryse-Phillips W, Risch N, et al (1996) A full genome search in multiple sclerosis. Nat Genet 13: 472–476.

    Article  PubMed  CAS  Google Scholar 

  • Evavold BD, Sloan-Lancaster J, Allen PM (1993) Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today 14: 602–609.

    Article  PubMed  CAS  Google Scholar 

  • Evavold BD, Sloan-Lancaster J, Wilson KJ, Rothbard JB, Allen PM (1995) Specific T cell recognition of minimally homologous peptides: evidence for endogenous ligands. Immunity 2: 655–663.

    Article  PubMed  CAS  Google Scholar 

  • Fritz RB, Skeen MJ, Jen-Chou CH, Garcia M, Egorov IK (1985) Major histocompatibility complex-linked control of the murine immune response to myelin basic protein. J Immunol 134: 2328–2332.

    PubMed  CAS  Google Scholar 

  • Fujinami RS, Oldstone MBA (1985) Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230: 1043–1045.

    Article  PubMed  CAS  Google Scholar 

  • Germain RN (1994) MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 76: 287–299.

    Article  PubMed  CAS  Google Scholar 

  • Germain RN, Margulies DH (1993) The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 11: 403–450.

    Article  PubMed  CAS  Google Scholar 

  • Goverman J, Woods A, Larson L, Weiner L, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72: 551–560.

    Article  PubMed  CAS  Google Scholar 

  • Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H, Pericak-Vance MA, Rimmler JB, Haynes CS, Roses AD, Lee A, Shaner B, Menold M, Seboun E, Fitoussi RP, Gartioux C, Reyes C, Ribierre F, Gyapay G, Weissenbach J, Hauser SL, Goodkin DE, Lincoln R, Usuku K, Oksenberg JR et al (1996) A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. Nat Genet 13: 469–471.

    Article  PubMed  CAS  Google Scholar 

  • Hao Q, Saida T, Kawakami H, Mine H, Maruya E, Inoko H, Saji H (1992) HLAs and genes in Japanese patients with multiple sclerosis: evidence for increased frequencies of HLA-Cw3, HLA-DR2, and HLA-DQBl*0602. Hum Immunol 35: 116–124.

    Article  PubMed  CAS  Google Scholar 

  • Hemmer B, Fleckenstein BT, Vergelli M, Jung G, McFarland H, Martin R, Wiesmueller KH (1997) Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J Exp Med 185: 1651–1659.

    Article  PubMed  CAS  Google Scholar 

  • Hemmer B, Vergelli M, Gran B, Ling N, Conlon P, Pinilla C, Houghten R, McFarland HF, Martin R (1998a) Cutting edge: predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology. J Immunol 160: 3631–3636.

    PubMed  CAS  Google Scholar 

  • Hemmer B, Vergelli M, Pinilla C, Houghten R, Martin R (1998b) Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunol Today 19: 163–168.

    Article  PubMed  CAS  Google Scholar 

  • Houghten RA, Pinilla C, Blondelle SE, Appel JR, Dooley CT, Cuervo JH (1991) Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354: 84–86.

    Article  PubMed  CAS  Google Scholar 

  • Kuokkanen S, Sundvall M, Terwilliger JD, Tienari PJ, Wikstrom J, Holmdahl R, Pettersson U, Peltonen L (1996) A putative vulnerability locus to multiple sclerosis maps to 5pl4-pl2 in a region syntenic to the murine locus Eae2. Nat Genet 13: 477–480.

    Article  PubMed  CAS  Google Scholar 

  • Kurtzke J (1985) Epidemiology of multiple sclerosis. In: Vinken PJ, Bruyn GB, Klawans HL, et al (eds) Handbook of clinical neurology, vol 3: Demyelinating diseases. Elsevier, Amsterdam, pp 259–287.

    Google Scholar 

  • Kurtzke JF (1993) Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 6: 382–427.

    PubMed  CAS  Google Scholar 

  • Marrosu MG, Muntoni F, Murru MR, Spinicci G, Pischelda MP, Goddi F, Cossu P, Pirastu M (1988) Sardinian multiple sclerosis is associated with HLA-DR4: a serological and molecular analysis. Neurology 38: 1749–1753.

    PubMed  CAS  Google Scholar 

  • Martin R, McFarland HF (1997) Immunology of multiple sclerosis and experimental allergic encephalomyelitis. In: Raine CS, McFarland HF, Tourtellotte WW (eds) Multiple sclerosis: clinical and pathogenetic basis. Chapman Hall, London, pp 221–242.

    Google Scholar 

  • Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10: 153–187.

    Article  PubMed  CAS  Google Scholar 

  • Nossal GJ (1994) Negative selection of lymphocytes. Cell 76: 229–239.

    Article  PubMed  CAS  Google Scholar 

  • Oldstone MB (1987) Molecular mimicry and autoimmune disease. Cell 50: 819–820.

    Article  PubMed  CAS  Google Scholar 

  • Pinilla C, Appel JR, Houghten RA (1994) Investigation of antigen-antibody interactions using a soluble, non-support-bound synthetic decapeptide library composed of four trillion (4 X 10(12)) sequences. Biochem J 301: 847–853.

    PubMed  CAS  Google Scholar 

  • Raine CS (1997) 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. Chapman Hall, London, pp 243–286.

    Google Scholar 

  • Rammensee HG, Friede T, Stevanovic S (1995) MHC ligands and peptide motifs: first listing. Immunogenetics 41: 178–228.

    Article  PubMed  CAS  Google Scholar 

  • Remlinger J (1905) Accidents paralytiques au cours du traitment antirabique. Ann Inst Pasteur 19: 625–646.

    Google Scholar 

  • Rivers TM, Sprunt DH, Berry GP (1993) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58: 39–53.

    Article  Google Scholar 

  • Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, Robertson N, Clayton D, Goodfellow PN, Compston A (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 13: 464–468.

    Article  PubMed  CAS  Google Scholar 

  • Schlüsener H, Wekerle H (1985) Autoaggressive T lymphocyte lines recognize the encephalitogenic region of myelin basic protein; in vitro selection from unprimed rat T lymphocyte populations. J Immunol 135: 3128–3133.

    Google Scholar 

  • Vartdal F, Sollid LM, Vandvik B, Markussen G, Thorsby E (1989) Patients with multiple sclerosis carry DQB1 genes which encode shared polymorphic aminoacid sequences. Hum Immunol 25: 103–110.

    Article  PubMed  CAS  Google Scholar 

  • Vergelli M, Hemmer B, Utz U, Vogt A, Kalbus M, Tranquill L, Conlon P, Ling N, Steinman L, McFarland HF, Martin R (1996) Differential T cell activation by altered peptide ligands derived from myelin basic protein peptide (87–99). Eur J Immunol 26: 2624–2634.

    Article  PubMed  CAS  Google Scholar 

  • Vergelli M, Hemmer B, Kalbus M, Vogt A, Ling N, Conlon P, Coligan JE, McFarland HF, Martin R (1997) Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells. J Immunol 158: 3746–3752.

    PubMed  CAS  Google Scholar 

  • Vogt AB, Kropshofer H, Kaibacher 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 

  • von Boehmer H (1994) Positive selection of lymphocytes. Cell 76: 219–228.

    Article  Google Scholar 

  • Wucherpfennig KW, Strominger JL (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80: 695–705.

    Article  PubMed  CAS  Google Scholar 

  • Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, Hafler DA (1994) 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 179: 279–290.

    Article  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.

    Article  PubMed  CAS  Google Scholar 

  • Zinkernagel RM, Doherty PC (1974) Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248: 701–702.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cellular Immunology Section, Neuroimmunology Branch, NINDS, National Institutes of Health, Building 10, Room 5B-16, 10 Center Dr MSC 1400, Bethesda, MD, 20892, USA

    B. Gran, B. Hemmer & R. Martin M.D.

  2. Department of Neurology, University of Maryland at Baltimore Medical School, Baltimore, MD, USA

    R. Martin M.D.

Authors
  1. B. Gran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Hemmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Martin M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Universitätsklinik für Neurologie, Innsbruck, Österreich

    W. Poewe  & G. Ransmayr  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag/Wien

About this paper

Cite this paper

Gran, B., Hemmer, B., Martin, R. (1999). Molecular mimicry and multiple sclerosis — a possible role for degenerate T cell recognition in the induction of autoimmune responses. In: Poewe, W., Ransmayr, G. (eds) Advances in Research on Neurodegeneration. 6th International Winter Conference on N eurodegeneration, vol 55. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6369-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-6369-6_3

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-83261-5

  • Online ISBN: 978-3-7091-6369-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation