Abstract
The MHC region on human chromosome 6p21 is a critical susceptibility locus for many human autoimmune diseases. Susceptibility to a number of these diseases, including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, is associated with particular alleles of HLA-DR or HLA-DQ genes. Crystal structures of HLA-DR and HLA-DQ molecules with bound peptides from candidate autoantigens have demonstrated that critical polymorphic residues determine the shape and charge of key pockets of the peptide binding site and thus determine the interaction of these MHC molecules with peptides. These data provide strong support for the hypothesis that these diseases are peptide-antigen driven. In HLA-DR associated autoimmune diseases such as rheumatoid arthritis and pemphigus vulgaris, key polymorphic determinants are primarily localized to the P4 pocket of the binding site and determine whether the pocket has a positive or negative charge. Peptide binding studies have demonstrated that these changes in the P4 pocket have a significant impact on the repertoire of self-peptides that can be presented by these MHC class II molecules. In HLA-DQ associated diseases such as type 1 diabetes and celiac disease, the α57 polymorphism is critical for peptide presentation since it determines the charge of the P9 pocket of the binding site. The crystal structure of HLA-DQ8 demonstrated that the P9 pocket has a positive charge in HLA-DQ molecules associated with type 1 diabetes, due to the absence of a negative charge at P57. Striking structural similarities were identified between the human DQ8 and murine I-Ag7 molecules that confer susceptibility to type 1 diabetes, indicating that similar antigen presentation events may be relevant in humans and the NOD mouse model. Recent studies in the NOD mouse indicated that I-g7 can promote expansion in the thymus of a CD4 T cell population which recognizes a peptide ligand that stimulates a panel of islet-specific T cell clones. MHC class II molecules that confer susceptibility to an autoimmune disease may thus promote positive selection of potentially pathogenic T cell population in the thymus and later induce the differentiation of these cells into effector populations by presentation of peptides derived from the target organ.
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Wucherpfennig, K.W. (2006). HLA and Autoimmunity. In: Immunogenetics of Autoimmune Disease. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-39926-3_1
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DOI: https://doi.org/10.1007/978-0-387-39926-3_1
Publisher Name: Springer, Boston, MA
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