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Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis

Abstract

B10.RIII mice develop chronic and relapsing experimental autoimmune encephalomyelitis (EAE) after immunization with the myelin basic protein (MBP) peptide 89–101. The disease is associated with the major histocompatibility complex (MHC) (eae1). We have now investigated the importance of non–MHC regions for the EAE susceptibility in a cross between RIIIS/J and B10.RIII mice which share the MHC region but differ in disease susceptibility. Linkage analysis using microsatellite markers spanning the genome identified a region (eae2) on chromosome 15 which showed linkage to disease (P=0.0002). Our data also suggest linkage to a second region (eae3) on chromosome 3 (P=0.0024), and provide evidence for locus interactions between eae2 and eae3. These results provide clues to the genetic basis of multiple sclerosis.

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References

  1. Zamvil, S.S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. A. Rev. Immunol. 8, 579–621 (1990).

    Article  CAS  Google Scholar 

  2. Jansson, L., Olsson, T., Höjeberg, B. & Holmdahl, R. Chronic experimental autoimmune encephalomyelitis induced by the 89-101 myelin basic protein peptide in B10RIII (H-2r) mice. Eur. J. Immunol. 21, 693–699 (1991).

    Article  CAS  Google Scholar 

  3. Zhao, M.L., Xia, J.Q. & Fritz, R.B. Epitope specificity and TCR V beta gene utilization in the encephalitogenic response of B10. RIII(71 NS)/SnJ mice. J. Neuroimmunol. 42, 209–214 (1993).

    Article  CAS  Google Scholar 

  4. Offner, H. et al. T cell determinants of myelin basic protein include a unique encephalitogenic l-E-restricted epitopefor Lewis rats. J. exp. Med. 170, 355–367 (1989).

    Article  CAS  Google Scholar 

  5. Sakai, K. et al. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J. Neuroimmunol. 19, 21–32 (1988).

    Article  CAS  Google Scholar 

  6. Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183–187 (1990).

    Article  CAS  Google Scholar 

  7. Fritz, R.B., Skeen, M.J., Chou C, H.J., Garcia, M. & Egorov, I.K. Major histocompatibility complex-linked control of the murine immune response to myelin basic protein. J. Immunol. 134, 2328–2332 (1985).

    CAS  PubMed  Google Scholar 

  8. Montgomery, I.N. & Rauch, H.C. Experimental allergic encephalomyelitis (EAE) in mice:primary control of EAE susceptibility is outside the H-2 complex. J. Immunol. 128, 421–425 (1982).

    CAS  PubMed  Google Scholar 

  9. Gasser, D.L., Palm, J. & Gonatas, N.K. Genetic control of susceptibility to experimental allergic encephalomyelitis and the Ag-B locus of rats. J. Immunol. 115, 431–433 (1975).

    CAS  PubMed  Google Scholar 

  10. Vincek, V., Sertic, J., Zakeska-Rutczynska, Z., Figueroa, F. & Klein, J. Characterization of H-2 congenic strains using DNA markers. Immunogenetics 31, 45–51 (1990).

    Article  CAS  Google Scholar 

  11. Jansson, L., Olsson, T. & Holmdahl, R. Influence of T cell receptor genes on chronic experimental autoimmune encephalomyelitis. Immunogenetics 37, 466–468 (1993).

    Article  CAS  Google Scholar 

  12. Holmdahl, R. et al. Chronicity of tissue-specific experimental autoimmune disease. A role for B cells?. Immunol. Rev. 144, 109–135 (1995).

    Article  CAS  Google Scholar 

  13. Dietrich, W.F. et al. A genetic map of the mouse with 4006 simple sequence length polymorphisms. Nature Genet. 7, 220–225 (1994).

    Article  CAS  Google Scholar 

  14. Lander, E.S. et al. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1, 174–181 (1987).

    Article  CAS  Google Scholar 

  15. Bernard, C. & . Kelero de Rosbo, N. Multiple sclerosis: an autoimmune disease of multifactorial etiology. Curr. Opin. Immunol. 4, 760–765 (1992).

    Article  CAS  Google Scholar 

  16. Gearing, D.P. et al. The Leukemia Inhibitory Factor receptor (LIFR) gene is located within a cluster of cytokine receptor loci on mouse chromosome 15 and human chromosome 5p12-p13. Genomics 18, 148–150 (1993).

    Article  CAS  Google Scholar 

  17. Hayakava, J.-i., Nikaido, H. & Koizumi, T. Assignment of the gene locus for sixth component (C6) of complement in mice to chromosome 15. Immunogenetics 22, 637–642 (1985).

    Article  Google Scholar 

  18. Orren, A., Hobart, M.J., Nash, H.R. & Lachmann, P.J. Close linkage between mouse genes determining the two forms of complement component C6 and component C7, and Cis action of a C6 regulatory gene. Immunogenetics 21, 591–599 (1985).

    Article  CAS  Google Scholar 

  19. Copeland, N.G. et al. A genetic linkage map of the mouse: current applications and future prospects. Science 262, 57–66 (1993).

    Article  CAS  Google Scholar 

  20. Barker, S.C. et al. Activation of the prolactine receptor gene by promoter insertion in a moloney murine leukemia virus-induced rat thymoma. J. Virol. 66, 6763–6768 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Oakey, R.J., Howard, A., Hogarth, P.M. & Seldin, F. Chromosomal mapping of the high afinity Fc gamma receptor gene. Immunogenetics 35, 279–282 (1992).

    Article  CAS  Google Scholar 

  22. Kluck, P.M.C. The human interleukin-6 receptor α chain gene is localized on chromosome 1 band q21. Hum. Genet. 90, 542–544 (1993).

    Article  CAS  Google Scholar 

  23. Buchberg, A.M., Jenkins, N.A. & Copeland, N.G. Localization of the murine macrophage colony-stimulating factor to Chromosome 3 using interspecific backcross analysis. Genomics 5, 363–367 (1989).

    Article  CAS  Google Scholar 

  24. Prins, J.-B. et al. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice. Science 260, 695–698 (1993).

    Article  CAS  Google Scholar 

  25. Myers, K.J., Sprent, J., Dougherty, J.P. & Ron, Y. Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 41, 1–8 (1992).

    Article  CAS  Google Scholar 

  26. Lee, N.E. et al. Murine T cell receptor beta chain is encoded on chromosome 6. J. exp. Med. 160, 905–913 (1984).

    Article  CAS  Google Scholar 

  27. Haqqi, T.M., Banerjee, S., Anderson, G.D. & David, C.S. RIII S/J (H-2r). An inbred mouse strain with a massive deletion of T cell receptor Vß genes. J. exp. Med. 169, 1903–1909 (1989).

    Article  CAS  Google Scholar 

  28. Jouvin-Marche, E. et al. Complexity, polymorphism, and recombination of mouse T-cell receptor alpha gene families. Immunogenetics 30, 99–104 (1989).

    Article  CAS  Google Scholar 

  29. Tienari, P.J., Wikstrom, J., Sajantila, A., Palo, J. & Peltonen, L. Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Lancet 340, 987–991 (1992).

    Article  CAS  Google Scholar 

  30. Tienari, P.J., Terwilliger, J.D., Ott, J., Palo, J. & Peltonen, L. Two-locus linkage analysis in multiple sclerosis (MS). Genomics 19, 320–325 (1994).

    Article  CAS  Google Scholar 

  31. Thomson, G. Identifying complex disease genes: progress and paradigms. Nature Genet. 8, 108–110 (1994).

    Article  CAS  Google Scholar 

  32. Todd, J.A. et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351, 542–547 (1991).

    Article  CAS  Google Scholar 

  33. Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 371, 130–136 (1994).

    Article  CAS  Google Scholar 

  34. Laird, P. et al. A simplified mammalian DNA isolation procedure. Nucl. Acids Res. 19, 4293 (1991).

    Article  CAS  Google Scholar 

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Sundvall, M., Jirholt, J., Yang, HT. et al. Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis. Nat Genet 10, 313–317 (1995). https://doi.org/10.1038/ng0795-313

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