Functional epistasis on a common MHC haplotype associated with multiple sclerosis
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Functional epistasis on a common MHC haplotype associated with multiple sclerosis. / Gregersen, Jon Waarst; Kranc, Kamil R; Ke, Xiayi; Svendsen, Pia; Madsen, Lars S; Thomsen, Allan Randrup; Cardon, Lon R; Bell, John I; Fugger, Lars Henrik.
In: Nature, Vol. 443, No. 7111, 2006, p. 574-7.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Functional epistasis on a common MHC haplotype associated with multiple sclerosis
AU - Gregersen, Jon Waarst
AU - Kranc, Kamil R
AU - Ke, Xiayi
AU - Svendsen, Pia
AU - Madsen, Lars S
AU - Thomsen, Allan Randrup
AU - Cardon, Lon R
AU - Bell, John I
AU - Fugger, Lars Henrik
N1 - Keywords: Alleles; Animals; CD4-Positive T-Lymphocytes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Epistasis, Genetic; HLA-DR2 Antigen; Haplotypes; Humans; Linkage Disequilibrium; Mice; Multiple Sclerosis
PY - 2006
Y1 - 2006
N2 - 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 sclerosis, 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.
AB - 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 sclerosis, 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.
U2 - 10.1038/nature05133
DO - 10.1038/nature05133
M3 - Journal article
C2 - 17006452
VL - 443
SP - 574
EP - 577
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7111
ER -
ID: 9701200