Non-Myelin Antigen Autoreactivity in Multiple Sclerosis

  • G. Ristori
  • C. Montesperelli
  • C. Buttinelli
  • L. Battistini
  • S. Cannoni
  • G. Borsellino
  • R. Bomprezzi
  • A. Perna
  • M. Salvetti
Part of the Topics in Neuroscience book series (TOPNEURO)


Immune-mediated damage is probably the most relevant event among those that contribute to the pathogenesis of multiple sclerosis (MS). The search for autoantigens inducing T cell responses in MS as well as in other immune-mediated, organ-specific diseases was initated as soon as efficient techniques for the isolation and expansion of antigen-specific T cell lines became available [1].


Multiple Sclerosis Heat Shock Protein Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Multiple Sclerosis Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pette M, Fujita K, Kitze B et al. (1990) Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 40(11): 1770–1776PubMedCrossRefGoogle Scholar
  2. 2.
    Vergelli M (1999) Myelin antigen autoreactivity in multiple sclerosis. In: Martino G, Adorini L (eds) From basic immunology to immune-mediated demyelination (Topics in neuroscience, vol 2). Springer, Milan, pp 170–184CrossRefGoogle Scholar
  3. 3.
    Uccelli A (1999) Animal models of Demyelination of the central nervous system. In: Martino G, Adorini L (eds) From basic immunology to immune-mediated demyelination (Topics in neuroscience, vol 2). Springer, Milan, pp 233–245CrossRefGoogle Scholar
  4. 4.
    Hohlfeld R (1997) Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120: 865–916PubMedCrossRefGoogle Scholar
  5. 5.
    Brosnan CF, Selmaj K, Raine CS (1988) Hypothesis: a role for tumor necrosis factor in immune-mediated demyelination and its revelance to multiple sclerosis. J Neuroimmunol 18: 87–94PubMedCrossRefGoogle Scholar
  6. 6.
    Selmaj KW, Raine CS (1988) Tumor necrosis factors mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23: 339–46PubMedCrossRefGoogle Scholar
  7. 7.
    Selmaj K, Raine CS, Farooq M et al. (1991) Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol 147:1522–1529PubMedGoogle Scholar
  8. 8.
    Lowenstein CJ, Snyder SH (1992) Nitric oxide, a novel biologic messenger. Cell 70:705–707PubMedCrossRefGoogle Scholar
  9. 9.
    Choi DW (1993) Nitric oxide: Foe or a friend to the injured brain? Proc Natl Acad Sci USA 90: 9741–9743PubMedCrossRefGoogle Scholar
  10. 10.
    Liu J, Zhao M-L, Brosnan CF, Lee SC (1996) Expression of the type II nitric oxide synthase in primary human astrocytes and microglia: Role of IL-Iß and IL-1 receptor antagonist. J Immunol 157: 3569–3576PubMedGoogle Scholar
  11. 11.
    Selmaj K, Raine CS, Cannella B, Brosnan CF (1991) Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 87: 949–954PubMedCrossRefGoogle Scholar
  12. 12.
    Cannella B, Raine CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37: 424–435PubMedCrossRefGoogle Scholar
  13. 13.
    Scolding N, Franklin R (1998) Axon loss in multiple sclerosis. Lancet 352: 340–341PubMedCrossRefGoogle Scholar
  14. 14.
    Trapp BD, Peterson J, Ransohoff RM et al. (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338: 278–285PubMedCrossRefGoogle Scholar
  15. 15.
    Kojima K, Berger T, Lassmann H et al. (1994) Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S-100ß molecule, a calcium binding protein of astroglia. J Exp Med 180: 817–829PubMedCrossRefGoogle Scholar
  16. 16.
    Amor S, Baker D, Layward L et al. (1997) Multiple sclerosis: variations on a theme. Immunol Today 18: 368–371PubMedCrossRefGoogle Scholar
  17. 17.
    Sercarz EE, Lenhmann PV, Ametani A et al. (1993) Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11: 729–766PubMedCrossRefGoogle Scholar
  18. 18.
    Miller SD, McRae BL, Vanderlugt CL et al. (1995) Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol Rev 144: 225–244PubMedCrossRefGoogle Scholar
  19. 19.
    Tian J, Lehmann PV, Kaufman DL (1997) Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens. J Exp Med 186(12): 2039–2043PubMedCrossRefGoogle Scholar
  20. 20.
    Tuohy VK, Yu M, Weinstock-Guttman B, Kinkel RP (1997) Diversity and plasticity of self recognition during the development of multiple sclerosis. J Clin Invest (7): 1682–1690Google Scholar
  21. 21.
    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(5): 695–705PubMedCrossRefGoogle Scholar
  22. 22.
    Hemmer B, Fleckenstein BT, Vergelli M et al. (1997) Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J Exp Med 185(9): 1651–1659PubMedCrossRefGoogle Scholar
  23. 23.
    Mason D (1998) A very high level of cross reactivity is an essential feature of the T-cell receptor. Immunol today 19: 395–404PubMedCrossRefGoogle Scholar
  24. 24.
    Fiori P, Ristori G, Cacciani A et al. (1997) Down-regulation of cell-surface CD4 coreceptor expression and modulation of experimental allergic encephalomyelitis. Int Immunol 9(4): 541–545PubMedCrossRefGoogle Scholar
  25. 25.
    Young RA (1990) Stress proteins and immunology. Annu Rev Immunol 8: 401–420PubMedCrossRefGoogle Scholar
  26. 26.
    Wekerle H (1998) The viral triggering of autoimmune disease. Nat Med 4(7): 770–771PubMedCrossRefGoogle Scholar
  27. 27.
    Horwitz MS, Bradley LM, Harbertson J et al. (1998) Coxsackie virus-induced diabet: Initation by bystander damage and not molecular mimicry. Nat Med 4: 781–785PubMedCrossRefGoogle Scholar
  28. 28.
    Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I restricted CTLs. Nature 392: 86–89PubMedCrossRefGoogle Scholar
  29. 29.
    van Eden W, van der Zee R, Paul AG et al. (1998) Do heat shock proteins control the balance of T-cell regulation in inflammatory diseases? Immunol Today 19(7): 303–307PubMedCrossRefGoogle Scholar
  30. 30.
    Newcomb JR, Cresswell P (1993) Characterization of endogenous peptides bound to purified HLA-DR molecules and their absence from invariant chain-associated alpha beta dimers. J Immunol 150(2): 499–507PubMedGoogle Scholar
  31. 31.
    Gupta RS, Golding GB (1993) Evolution of HSP70 gene and its implications regarding relationships between archaebacteria, eubacteria, and eukaryotes. J Mol Evol 37(6): 573–582PubMedCrossRefGoogle Scholar
  32. 32.
    Mayer RJ, Brown IR (1994) Heat shock proteins in the nervous system. Academic Press, LondonGoogle Scholar
  33. 33.
    D’Souza SD, Antel JP, Freedman MS (1994) Cytokine induction of heat shock protein expression in human oligodendrocytes: An interleukin-1 mediated mechanism. J Neuroimmunol 50:17–24PubMedCrossRefGoogle Scholar
  34. 34.
    Satoh J, Kim SU (1995) Constitutive and inducible expression of heat shock protein HSP72 in oligodendrocytes in culture. Neuroreport 6: 1081–1084PubMedCrossRefGoogle Scholar
  35. 35.
    Aquino DA, Lopez C, Farooq M (1996) Antisense oligonucleotide to the 70-kDa heat shock protein inhibits synthesis of myelin basic protein. Neurochem Res 21: 417–422PubMedCrossRefGoogle Scholar
  36. 36.
    Brosnan CF, Battistini L, Gao YL et al. (1996) Heat shock proteins and multiple sclerosis. J Neuropathol Exp Neurol 55: 389–402PubMedCrossRefGoogle Scholar
  37. 37.
    Aquino DA, Klipfel AA, Brosnan CF, Norton WT (1993) The 70 kDa heat shock cognate protein is a major constituent of the central nervous system and is upregulated only at the mRNA level in acute experimental autoimmune encephalomyelitis. J Neurochem 61:1340–1348PubMedCrossRefGoogle Scholar
  38. 38.
    Gao YL, Brosnan CF, Raine CS (1995) Experimental autoimmune encephalomyelitis. Qualitative and quantitative differences in heat shock protein 60 expression in the central nervous system. J Immunol 154: 3448–3456Google Scholar
  39. 39.
    Koga T, Wand-Wurttenberger A, de Bruyn J et al. (1989) T cells against a bacterial heat shock protein recognize stressed macrophages. Science 246:1112–1115CrossRefGoogle Scholar
  40. 40.
    Aquino DA, Capello E, Weisstein J et al. (1997) Multiple sclerosis: altered expression of 70- and 27-kDa heat shock proteins in lesions and myelin. J Neuropathol Exp Neurol 56: 664–672PubMedGoogle Scholar
  41. 41.
    Bajramovic JJ, Lassmann H, van Noort JM (1997) Expression of αB-crystallin in glia cells during lesional development in multiple sclerosis. J Neuroimmunol 78: 143–151PubMedCrossRefGoogle Scholar
  42. 42.
    Mor F, Cohen IR (1992) T cells in the lesion of experimental autoimmune encephalomyelitis. Enrichment for reactivities to myelin basic protein and to heat shock protein. J Clin Invest 90: 2447–2455PubMedCrossRefGoogle Scholar
  43. 43.
    Birnbaum G, Kotilinek L, Schlievert P et al. (1996) Heat shock proteins and experimental autoimmune encephalomyelitis (EAE): I. Immunization with a peptide of the myelin protein 2′, 3′ cyclic nucleotide 3′ phosphodiesterase that is cross-reactive with a heat shock protein alters the course of EAE. J Neurosci Res 44(4): 381–396PubMedCrossRefGoogle Scholar
  44. 44.
    Salvetti M, Buttinelli C, Ristori G et al. (1992) T-lymphocyte reactivity to the recombinant mycobacterial 65- and 70-kD heat shock proteins in multiple sclerosis. J Autoimmunity 5: 691–702CrossRefGoogle Scholar
  45. 45.
    Salvetti M, Ristori G, Buttinelli C et al. (1996) The immune response to mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis. J Neuroimmunol 65: 143–153PubMedCrossRefGoogle Scholar
  46. 46.
    Stinissen P, Vandevyver C, Medaer R et al. (1995) Increased frequency of γδ T cells in the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis: reactivity, cytotoxicity and T cell receptor V gene rearrangements. J Immunol 154:4883–4894PubMedGoogle Scholar
  47. 47.
    van Noort JM, van Sechel AC, Bajramovic JJ et al. (1995) The small heat shock protein alpha-B crystallin as a candidate autoantigen in multiple sclerosis. Nature 375:798–801PubMedCrossRefGoogle Scholar
  48. 48.
    van Sechel AC, van Stipdonk MJB, Persoon-Deen C, van Noort JM (1998) Epstein-Barr virus induced expression and HLA-DR restricted presentation of αB-crystallin, a major human myelin antigen. J Neuroimmunol 90: 38 (abstract)CrossRefGoogle Scholar
  49. 49.
    Banki K, Colombo E, Sia F et al. (1994) Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis. J Exp Med 180: 1649–1663PubMedCrossRefGoogle Scholar
  50. 50.
    Colombo E, Banki K, Tatum AH et al. (1997) Comparative analysis of antibody and cell-mediated autoimmunity to transaldolase and myelin basic protein in patients with multiple sclerosis. J Clin Invest 99: 1238–1250PubMedCrossRefGoogle Scholar
  51. 51.
    Walsh MJ, Murray JM (1998) Dual implication of 2′,3′-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis. J Clin Invest 101(9): 1923–1931PubMedCrossRefGoogle Scholar
  52. 52.
    Giulian D, Moore S (1980) Identification of 2′,3′ cyclic nucleotide 3′-phosphodiesterase in the vertebrate retina. J Biol Chem 255: 5993–5995PubMedGoogle Scholar
  53. 53.
    Tola MR, Granieri E, Casetta I et al. (1993) Retinal periphlebitis in multiple sclerosis: a marker of disease activity. Eur Neurol 33: 93–96PubMedCrossRefGoogle Scholar
  54. 54.
    Selmaj K, Brosnan CF, Raine CS (1991) Colocalization of lymphocytes bearing the γδ T cell receptor and heat shock protein 65+ oligodendrocytes in multiple sclerosis. Proc Natl Acad Sci USA 88: 6452–6456PubMedCrossRefGoogle Scholar
  55. 55.
    Battistini L, Fischer FR, Raine CS, Brosnan CF (1996) CD1b is expressed in multiple sclerosis lesions. J Neuroimmunol 67(2): 145–151PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 1999

Authors and Affiliations

  • G. Ristori
    • 1
  • C. Montesperelli
    • 1
  • C. Buttinelli
    • 1
  • L. Battistini
    • 2
  • S. Cannoni
    • 1
  • G. Borsellino
    • 2
  • R. Bomprezzi
    • 1
  • A. Perna
    • 1
  • M. Salvetti
    • 1
  1. 1.Department of Neurological SciencesUniversity of Rome La SapienzaRomeItaly
  2. 2.IRCCS Santa LuciaRomeItaly

Personalised recommendations