Autoimmunity,Self-Tolerance,and MHC Class I Expression

Abstract

Background: The major histocompatibility complex class II gene products are genetically linked to a diversity of autoimmune diseases. This has resulted in the belief that abnormal MHC class II gene function or aberrant expression is the primary cause of autoimmunity. In the case of type I diabetes, the insulin secreting islets of Langerhans are destroyed and a specific amino acid substitution in the MHC class II gene, DQβ has the strongest genetic linkage with disease penetrance. Methods: Freshly prepared peripheral blood lymphocytes from type I diabetics as well as the NOD mouse, a murine model for autoimmune diabetes, were examined for proliferation to self antigens. Results: A defect in diabetic lymphocytes to properly recognize self antigens was localized to defective autologous antigen presentation on presenting cells such as B cells and macrophages; no defect was found in the proliferating T cells to autologous antigens. Furthermore, the diabetic autoimmune defect appeared to be due to the failure to present endogenous antigens for self tolerance in the groove of MHC class I. In the mouse and human, some of the genes that control proper MHC class I assembly are within the MHC class II gene region. In the NOD mouse, we demonstrate a unique RFLP pattern and decreased mRNA levels for one of these endogenous peptide supply factor genes. Conclusions: Autoimmune diabetes is characterized by decreased MHC class I expression on antigen presenting cells. MHC class I gene products are responsible for presentation of self antigens and this pathway appears to be essential for tolerance induction. The genetic linkage between autoimmune disease and MHC class II genes may be explained in part by abnormal MHC class II linked proteins that are necessary for MHC class I presentation of endogenous peptide fragments for self tolerance.