Functional epistasis on a common MHC haplotype associated with multiple sclerosis

Abstract

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.

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Acknowledgements

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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This file contains Supplementary Figures 1–5, Supplementary Table 1, Supplementary Methods and additional references. (PDF 1481 kb)

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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). https://doi.org/10.1038/nature05133

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