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Functional epistasis on a common MHC haplotype associated with multiple sclerosis


Genes in the major histocompatibility complex (MHC) encode proteins important in activating antigen-specific immune responses. Alleles at adjacent MHC loci are often in strong linkage disequilibrium; however, little is known about the mechanisms responsible for this linkage disequilibrium. Here we report that the human MHC HLA-DR2 haplotype, which predisposes to multiple sclerosis1,2,3, shows more extensive linkage disequilibrium than other common caucasian HLA haplotypes in the DR region and thus seems likely to have been maintained through positive selection. Characterization of two multiple-sclerosis-associated HLA-DR alleles at separate loci by a functional assay in humanized mice indicates that the linkage disequilibrium between the two alleles may be due to a functional epistatic interaction, whereby one allele modifies the T-cell response activated by the second allele through activation-induced cell death. This functional epistasis is associated with a milder form of multiple-sclerosis-like disease. Such epistatic interaction might prove to be an important general mechanism for modifying exuberant immune responses that are deleterious to the host and could also help to explain the strong linkage disequilibrium in this and perhaps other HLA haplotypes.

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Figure 1: Analysis of selection around HLA-DRB1 and HLA-DRB5 loci using extended haplotype homozygosity.
Figure 2: DR2a induces peripheral deletion of Hy + CD4 + T cells by AICD.


  1. Lincoln, M. R. et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nature Genet. 37, 1108–1112 (2005)

    Article  CAS  Google Scholar 

  2. Oksenberg, J. R. et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am. J. Hum. Genet. 74, 160–167 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Fernandez-Vina, M. A. et al. Alleles at four HLA class II loci determined by oligonucleotide hybridization and their associations in five ethnic groups. Immunogenetics 34, 299–312 (1991)

    Article  CAS  Google Scholar 

  5. Gao, X. J. & Serjeantson, S. W. Heterogeneity in HLA-DR2-related DR,DQ haplotypes in eight populations of Asia-Oceania. Immunogenetics 34, 401–408 (1991)

    Article  CAS  Google Scholar 

  6. Mehra, N. K. et al. Analysis of HLA-DR2-associated polymorphisms by oligonucleotide hybridization in an Asian Indian population. Hum. Immunol. 32, 246–253 (1991)

    Article  CAS  Google Scholar 

  7. Moraes, M. E., Fernandez-Vina, M. & Stastny, P. DNA typing for class II HLA antigens with allele-specific or group-specific amplification. IV. Typing for alleles of the HLA-DR2 group. Hum. Immunol. 31, 139–144 (1991)

    Article  CAS  Google Scholar 

  8. Gao, X. J. et al. DNA typing for HLA-DR, and -DP alleles in a Chinese population using the polymerase chain reaction (PCR) and oligonucleotide probes. Tissue Antigens 38, 24–30 (1991)

    Article  CAS  Google Scholar 

  9. Lee, A. et al. Heterogeneity of HLA-DR2 haplotypes in Caucasoid Americans, African Americans, Chinese Americans, Native Americans and Xiamen Chinese. Eur. J. Immunogenet. 26, 275–280 (1999)

    Article  CAS  Google Scholar 

  10. Song, E. Y., Kang, S. J., Lee, Y. J. & Park, M. H. HLA-DR2-associated DRB1 and DRB5 alleles and haplotypes in Koreans. Hum. Immunol. 61, 937–941 (2000)

    Article  CAS  Google Scholar 

  11. Miretti, M. M. et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 634–646 (2005)

    Article  CAS  Google Scholar 

  12. Bateson, W. Mendel's Principles of Heredity Ch. IV, 79 (Cambridge Univ. Press, Cambridge, 1909)

    Book  Google Scholar 

  13. Phillips, P. C. The language of gene interaction. Genetics 149, 1167–1171 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Walsh, E. C. et al. An integrated haplotype map of the human major histocompatibility complex. Am. J. Hum. Genet. 73, 580–590 (2003)

    Article  CAS  Google Scholar 

  15. Altshuler, D. et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

    Article  Google Scholar 

  16. Fogdell, A., Hillert, J., Sachs, C. & Olerup, O. The multiple sclerosis- and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 46, 333–336 (1995)

    Article  CAS  Google Scholar 

  17. Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  19. Lang, H. L. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nature Immunol. 3, 940–943 (2002)

    Article  CAS  Google Scholar 

  20. Madsen, L. S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Genet. 23, 343–347 (1999)

    Article  CAS  Google Scholar 

  21. Green, D. R., Droin, N. & Pinkoski, M. Activation-induced cell death in T cells. Immunol. Rev. 193, 70–81 (2003)

    Article  CAS  Google Scholar 

  22. Suvannavejh, G. C., Dal Canto, M. C., Matis, L. A. & Miller, S. D. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis. J. Clin. Invest. 105, 223–231 (2000)

    Article  CAS  Google Scholar 

  23. Ganem, D. & Prince, A. M. Hepatitis B virus infection—natural history and clinical consequences. N. Engl. J. Med. 350, 1118–1129 (2004)

    Article  CAS  Google Scholar 

  24. Ross, A. G. et al. Schistosomiasis. N. Engl. J. Med. 346, 1212–1220 (2002)

    Article  Google Scholar 

  25. Zinkernagel, R. M., Pfau, C. J., Hengartner, H. & Althage, A. Susceptibility to murine lymphocytic choriomeningitis maps to class I MHC genes—a model for MHC/disease associations. Nature 316, 814–817 (1985)

    Article  ADS  CAS  Google Scholar 

  26. Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002)

    Article  ADS  CAS  Google Scholar 

  27. Voight, B. F. et al. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006)

    Article  Google Scholar 

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We thank N. Willcox for discussion. Work in the authors' laboratories is supported by the Danish and British Medical Research Councils and the European Commission Descartes Prize (L.F. and J.I.B.); the Karen Elise Jensen Foundation, the Lundbeck Foundation and the Danish Multiple Sclerosis Society (L.F.); and the Wellcome Trust, the NIH and the European Union (L.R.C. and X.K.). Author Contributions J.W.G. and K.R.K. contributed equally to this work. J.I.B. and L.F. contributed equally to this work.

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Correspondence to Lars Fugger.

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Gregersen, J., Kranc, K., Ke, X. et al. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443, 574–577 (2006).

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