title: Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA.
abstract: 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.forename: Hiroko
authors.initials: H
authors.lastname: Miyadera
authors.forename: Jun
authors.initials: J
authors.lastname: Ohashi
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011110:Polymorphism, Genetic; D055550:Protein Stability
chemical_list: D006683:HLA-DQ Antigens