MHC structure and autoimmune T cell repertoire development

Recent work has continued to clarify the relationship between MHC structure and thymic selection that leads to peripheral T cell repertoire development in the pathogenesis of autoimmune diseases. Particular attention has been focused on the nonobese diabetic model of autoimmune diabetes, in which a unique MHC class II molecule (I-Ag7) plays a central role. In the past year, reports on the biochemistry of I-Ag7 — combined with analysis of the role of I-Ag7 in T cell repertoire selection — support a model of defective thymic selection as the basis of the association between particular MHC molecules and autoimmune diseases. Analogous work has been done on the structure of the human MHC disease-susceptible and -resistant alleles, DQA1*0301 DQB1*0302 and DQA1*0102 DQB1*0602, and their effect on autoimmune repertoire selection. Comparison of these results (in naturally occurring, spontaneous autoimmune human and murine diabetes), with results in a variety of transgenic and knockout models, has produced an integrated view of how avidity considerations in repertoire selection in the thymus could affect predisposition towards autoimmunity.