A strong genetic association exists between certain autoimmune diseases [HN1], such as rheumatoid arthritis [HN2], multiple sclerosis [HN3], and insulin-dependent diabetes mellitus (IDDM)[HN4], and the expression of certain kinds (haplotypes [HN5]) of major histocompatibility complexes (MHCs)[HN6](genes encoding cell-surface molecules that display peptides for immune recognition)(1). The current explanation for this association proposes that disease-associated MHC molecules efficiently bind autoantigens [HN7] involved in the pathophysiology of the disease. This results in a peripheral T cell-mediated immune response to the autoantigen and autoimmune sequelae [HN8].

Recent results in an animal model of autoimmune diabetes, the nonobese diabetic (NOD) mouse [HN9], however, suggest a new hypothesis to explain the role of MHC in autoimmunity. This hypothesis proposes that the genetic association between MHC and autoimmune disease results from “altered” thymic selection [HN10] in which high-affinity self-reactive (potentially autoreactive) T cells [HN11] escape selection in the thymus [HN12] as a result of the poor self peptide-binding properties of the disease-associated MHC class II molecules [HN13](2). This model offers an explanation for the unusual requirement of homozygous MHC class II expression in human IDDM and IDDM in NOD mice.