Many regions and loci of the murine genome contribute to the pancreatic and salivary gland autoimmunity observed in the diabetic NOD mouse. Examination of the major histocompatibility complex region of the NOD mouse has revealed a defect in the expression of the major histocompatibility complex class II gene, I-E. To determine the isolated role of faulty I-E expression in abnormal self-recognition, we examined six commonly used inbred strains of mice on diverse genetic backgrounds that also do not express I-E, i.e., C57BL/10, SJL, ACA, DBA/1, NOD, and 129. Autoimmunity was assessed by the presence of inflammatory cell infiltrates (0,+/-,+,++, , +) within and among the pancreatic islets and salivary glands, and autoantibodies to self determinants. At 6 mo of age, inflammatory infiltrates in the pancreas (0, 3 mice; +/-, 3 mice; +, 7 mice; ++, 6 mice; , 1 mouse; +, 5 mice) and/or salivary glands (0, 0 mice; +/-, 3 mice; +, 1 mouse; ++, 4 mice; , 6 mice; +, 10 mice) were detected as well as autoantibodies in all 24 mice of all I-E- mouse strains on diverse genetic backgrounds. This indicates that defective expression of this single locus, in isolation, is sufficient for the spontaneous development of autoreactivity. In contrast, the simultaneous examination of 19 I-E+ mice on five commonly used inbred strains of mice (BALB/c, C67/KsJ, B10.BR, B10.A [2R], and B10.A [5R]) demonstrated no signs of humoral or cellular autoimmunity with target gland destruction or lymphocytic invasion. Our data suggest that many commonly used inbred strains of mice represent models of autoimmunity attributable to this single defective gene.(ABSTRACT TRUNCATED AT 250 WORDS)