MHC class II proteins and disease: a structural perspective

Key Points The strength of the genetic association between specific MHC class II alleles and an individual's susceptibility to particular chronic inflammatory diseases renders these alleles the main known risk factor for many such diseases. The peptide-binding grooves of MHC class II molecules can be described in terms of pockets that must accommodate the side chains of residues at positions P1, P4, P6 and P9 of the peptide. Analyses of the characteristics of these pockets, as revealed by the crystal structures of MHC class II molecules, provide insights into how sequence polymorphisms determine the population of peptides a particular MHC class II molecule can bind, and indicate molecular mechanisms that could determine disease susceptibility. Structure-based analysis indicates that differential peptide binding between two closely related HLA-DQ6 molecules is central to their positive and negative association with the chronic neurological disorder narcolepsy, an observation that is consistent with narcolepsy being an autoimmune disease. Coeliac disease is an autoimmune-like disorder that is caused by an immune response to antigens present in wheat gluten. HLA-DQ2, and to a lesser extent HLA-DQ8, have peptide-binding-groove characteristics that strongly favour the binding of gluten-derived peptides, consistent with the association of these MHC class II molecules with coeliac disease. Crystal structures for the type-1-diabetes-associated MHC class II molecules HLA-DQ8, HLA-DQ2 and mouse H2-IA g7 reveal a distinctive P9 pocket, which might indicate similar pathophysiological pathways for developing type 1 diabetes in humans and non-obese diabetic mice. A comparison of the structures of disease-associated versus protective MHC class II molecules reveals a second characteristic; the P6 pocket shows a consistent trend in volume size that correlates from positive to negative association with type 1 diabetes. T cells are thought to play an important role in the development of rheumatoid arthritis and an immunodominant T-cell epitope from type II collagen is a candidate autoantigen. The structures of the disease-associated HLA-DR4.1 and HLA-DR1 molecules reveal P4 pockets that have in common an ability to bind acidic residues, plus shallow P6 and P9 pockets that are particularly well suited to binding the glycine-rich sequences typical of type-II-collagen-derived peptides. Distinctive structural characteristics of the multiple-sclerosis-associated MHC class II mole