Polymorphisms within HLA gene loci are strongly associated with susceptibility to autoimmune disorders; however, it is not clear how genetic variations in these loci confer a disease risk. Here, we devised a cell-surface MHC expression assay to detect allelic differences in the intrinsic stability of HLA-DQ proteins. We found extreme variation in cell-surface MHC density among HLA-DQ alleles, indicating a dynamic allelic hierarchy in the intrinsic stability of HLA-DQ proteins. Using the case-control data for type 1 diabetes (T1D) for the Swedish and Japanese populations, we determined that T1D risk–associated HLA-DQ haplotypes, which also increase risk for autoimmune endocrinopathies and other autoimmune disorders, encode unstable proteins, whereas the T1D–protective haplotypes encode the most stable HLA-DQ proteins. Among the amino acid variants of HLA-DQ, alterations in 47α, the residue that is located on the outside of the peptide-binding groove and acts as a key stability regulator, showed strong association with T1D. Evolutionary analysis suggested that 47α variants have been the target of positive diversifying selection. Our study demonstrates a steep allelic hierarchy in the intrinsic stability of HLA-DQ that is associated with T1D risk and protection, suggesting that HLA instability mediates the development of autoimmune disorders.
Authors
Hiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, Katsushi Tokunaga
(A) Peptide specificity model. This model postulates that the peptide-binding spectrum of the MHC determines the genetic association of HLA with autoimmunity. According to this model, the HLAs that are able to present the disease-relevant peptides (magenta) confer a risk for autoimmunity. Colors indicate the disease-relevant (magenta) and irrelevant peptides (white). (B) MHC stability model. This model postulates that intrinsically unstable MHC proteins (magenta), which form unstable MHC–self-epitope complexes through presentation of diverse self-peptides and are more likely to form unstable pMHC than intrinsically stable MHC, confer a risk for autoimmunity.