Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating neurological disease in which autoreactive T lymphocytes sensitized to myelin components of the central nervous system are postulated to contribute to pathogenesis. The possible relevance of molecular mimicry between a human coronavirus and the myelin basic protein component of myelin in the generation of this autoimmune reaction was evaluated. Myelin basic protein– and virus‐reactive T‐cell lines were established from 16 MS patients and 14 healthy donors and shown to be mostly CD4+. In contrast to healthy donors, several T‐cell lines isolated from MS patients showed cross‐reactivity between myelin and coronavirus antigens. Overall, 29% of T‐cell lines from MS patients (10 donors) but only 1.3% of T‐cell lines from normal control subjects (2 donors) showed an HLA‐DR‐restricted cross‐reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens. Moreover, reciprocal reactivities were only observed in MS patients (4 donors). This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease.
References
- 1. Ffrenchconstant C Pathogenesis of multiple sclerosis. Lancet 1994; 343: 271–175 [DOI] [PubMed] [Google Scholar]
- 2. Sadovnick AD, Ebers GC Epidemiology of multiple sclerosis‐a critical overview. Can J Neurol Sci 1993; 20: 17–29 [DOI] [PubMed] [Google Scholar]
- 3. Hillert J Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 1994; 36: S15–S17 [DOI] [PubMed] [Google Scholar]
- 4. Steinman L, Oksenherg JR, Bernard CCA Association of susceptibility to multiple sclerosis with TCR genes. Immunol Today 1992; 13: 49–51 [DOI] [PubMed] [Google Scholar]
- 5. Kurtzke JF Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 1993; 6: 382–427 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Talbot PJ Implication of viruses in multiple sclerosis. Médicine/Sciences 1995; 11: 837–843 [Google Scholar]
- 7. Myint SH Human coronavituses‐a brief review. Rev Med Virol 1994; 4: 35–46 [Google Scholar]
- 8. Murray RS, Cai GY, Hoek K, et al. Coronavirus infects and causes demyelination in primate central nervous system. Virology 1992; 188: 274–284 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Tanaka R, Iwasaki Y Koprowski HI Intracisternal virus‐like particles in the brain of a multiple sclerosis patient. J Neurosci Res 1976; 28: 121–126 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Burks JS, DeVald BL, Jankovsky LD, Gerdes JC Two coronavituses isolated from central nervous system tissue of two multiple sclerosis patients. Science 1980; 209: 933–934 [DOI] [PubMed] [Google Scholar]
- 11. Salmi A, Ziola B, Hovi T, Reunanen M Antibodies to coronaviruses OC43 and 229E in multiple sclerosis patients. Neurology 1982; 32: 292–295 [DOI] [PubMed] [Google Scholar]
- 12. Pearson J, Mims CA Differential susceptibility of cultured neural cells to the human coronavirus OC43. J Virol 1985; 53: 1016–1019, [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Talbot PJ, Ékandé S, Cashman NR, et al. Neurotropism of human coronavirus 229E. Adv Exp Med Biol 1994; 32: 339–346 [DOI] [PubMed] [Google Scholar]
- 14. Stewart JN, Mounir S, Talbot PJ Human coronavirus gene expression in the brains of multiple sclerosis patients. Virology 1992; 191: 502–505 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Murray RS, Brown B, Brian D, Cabirac GF Detection of coronavirus RNA and antigen in multiple sclerosis brain. Ann Neural 1992; 31: 525–533 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Zhang JW, Markovicplese S, Lacet B, et al. Increased frequency of interleukin 2‐responsive T cells specific for myelin basic protein and protealipid protein in peripheral blood and cerebro‐ spinal fluid of patients with multiple sclerosis. J Exp Med 1994; 179: 973–984 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Sun JB, Link H, Olsson T, et al. T‐cell and B‐cell responses to myelin‐oligodendrucyte glycoprotein in multipie sclerosis. J Immunol 1991; 146: 1490–1495 [PubMed] [Google Scholar]
- 18. Zhang Y, Burger D, Saruhan G, et al. The T‐lymphocyte response against myelin‐associated glycoprotein and myelin basic protein in patients with multiple sclerosis. Neurology 1993; 43: 403–407 [DOI] [PubMed] [Google Scholar]
- 19. Derosbo NK, Milo R, Lees MB, et al. Reactivity to myelin antigens in multiple sclerosis‐peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 1993; 92: 2602–2608 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Watanabe R, Wege H, ter Meulen V Adoptive transfer of EAE‐like lesions from rats with coronavirus‐induced demyelinating encephalomyelitis. Nature 1983; 305: 150–153 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Oldstone MBA Molecular mimicry and autoimmune disease. Cell 1987; 50: 819–820 [DOI] [PubMed] [Google Scholar]
- 22. Barnett LA, Fujinami RS Molecular mimicry: a mechanism for autoimmune injury. FASEB J 1992; 6: 840–844 [DOI] [PubMed] [Google Scholar]
- 23. Jahnke U, Fischer EH, Alvord EC Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis. Science 1985; 229: 282–284 [DOI] [PubMed] [Google Scholar]
- 24. Shaw SY, Laursen RA, Lees MB Analogous amino acid sequences in myelin proteolipid and viral proteins. FEBS Lett 1986; 207: 266–270 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Ota K, Matsui M, Milford EL, et al. T‐cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990; 346: 183–187 [DOI] [PubMed] [Google Scholar]
- 26. Jouvenne P, Mounir S, Stewart JN, et al. Sequence analysis of human coronavirus 229E messenger RNAs 4 and 5‐evidence for polymorphism and homology with myelin basic protein. Virus Res 1992; 22: 125–141 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Cheifetz S, Mascarello MA Effect of bovine basic protein charge microheterogencity on protein‐induced aggregation of unilamellar vesicles containing a mixture of acidic and neutral phospholipids. Biochemistry 1985; 24: 1909–1914 [DOI] [PubMed] [Google Scholar]
- 28. Mounir S, Talbot PJ Sequence analysis of the membrane protein gene of human coronavirus Oc43 and evidence for Oglycosylation. J Gen Viral 1992; 73: 2731–2736 [DOI] [PubMed] [Google Scholar]
- 29. Pette M, Fijita K, Kitze MD, et al. Myelin basic proteinspecific T lymphocyte lines from MS patients and healthy individuals. Neurology 1990; 40: 1770–1776 [DOI] [PubMed] [Google Scholar]
- 30. Richert JR, Reuben‐Burnside CA, Deibler GE, Kies MW Peptide specificities of myelin basic protein‐reactive human T‐cell clones. Neurology 1988; 38: 739–742 [DOI] [PubMed] [Google Scholar]
- 31. Inobe J‐I, Yamamura T, Kunishita T, Tabira T T lymphocyte lines and clones selected against synthetic myelin basic protein 82‐102 peptide from Japanese multiple sclerosis patients. J Neuroimmunol 1993; 46: 83–90 [DOI] [PubMed] [Google Scholar]
- 32. Labrecque N, McGrath H, Subramanyam M, et al. Human T cells respond to mouse mammary tumor virus encoded superantigen‐V‐beta restriction and conserved evolutionary features. J Exp Med 1993; 177: 1735–1743 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Matzinger P Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991–1045 [DOI] [PubMed] [Google Scholar]
- 34. Selin LK, Nahill SR, Welsh RM Cross‐reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J Exp Med 1994; 179: 1933–1943 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Gautam AM, Lock CB, Smilek DE, et al. Minimum structural requirements for peptide presentation by major histocompatibility complex class I1 molecules‐implications in induction of autoimmunity. Proc Natl Acad Sci USA 1994; 91: 767–771 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Wucherpfennig KW, Strominger JL Molecular mimicry in T‐ cell mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80: 695–705 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Wucherpfennig KW, Sette A, Southwood S, 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Riethmuller A, Kalbus M, Dubois E, et al. T‐cell‐reactivity against CNPase (a minor myelin component) in multiple sclerosis patienrs and normals. J Neuroimmunol 1994; 54: 191 [Google Scholar]
- 39. van Noort JM, van Sechel AC, Bajramovic JJ, et al. The small heat‐shock protein αB‐crystallin as candidate autoantigen in multiple sclerosis. Nature 1995; 375; 798–801 [DOI] [PubMed] [Google Scholar]
- 40. Panitch HS Influence of infection on exacerbations of multiple sclerosis. Ann Neural 1994; 36: S25–S28 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Duquette P, Girard M, Despault I, et al. Interferon beta‐lb is effective in relapsing‐remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double‐blind, placebo‐ controlled trial. Neurology 1993; 43: 655–661 [DOI] [PubMed] [Google Scholar]
- 42. Paty DW, Li DKB, Duquette P, et al. Interferon beta‐lb is effective in relapsing‐remitting multiple sclerosis. 11. MRI analysis results of a multicenter, randomized, double‐blind, placebo‐contrllokd trial. Neurology 1993; 43: 662–667 [DOI] [PubMed] [Google Scholar]
- 43. Jacobs L, Cookfair D, Rudick R, et al. Results of a phase 111 trial of IM recombinant beta interferon as treatment for MS. J Neuroimmunnl 1994; 54: 170 [Google Scholar]