2.5mi 5G 9D

An association between the HLA locus and autoimmune dysfunction was suggested as early as 1971. Later, attention focused on MHC class II genes with the discovery of an association between HLA-DR4 and rheumatoid arthritis in 1978. Thirty years have now passed since these seminal studies, and yet our general understanding of antigen presentation and T cell recognition at a molecular level has not provided an expected explanation for this association. One of the most striking examples of MHC allele linkage disequilibrium with autoimmune diseases is provided by type I diabetes (T1D) and the identification of a single residue polymorphism that confers either susceptibility or resistance to the disease. Indeed, almost all alleles linked to T1D share a common nonaspartic acid residue at position 57 of their β chain. The absence of a negative charge at β57 eliminates an interdomain salt bridge between Argα76 and β57; however, this substitution does not compromise the overall stability of the molecule or its capacity to bind peptide. The absence of a negative charge at β57 reshapes the P9 pocket of the HLA-DQ8/I-Ag7 peptide-binding groove and exposes a large positively charged patch on the MHC surface. An important functional consequence of this β57 polymorphism is a clear propensity for these MHC molecules to bind peptides with a negatively charged residue at position P9. However, this feature is not absolute and many noncharged P9 peptides efficiently bind diabetogenic MHC molecules, such as HLA-DQ8 or I-Ag7. These peptide-MHC (pMHC) complexes will as a result characteristically have an exposed positive P9 patch on the MHC surface due to the "unpaired" charged Argα76 residue.