Murine chronic graft vs host disease (GVHD) resembles human SLE in autoantibody specificities and glomerulonephritis. Chronic GVHD is induced by donor T cell recognition of recipient Ia Ag. This study compared the role of the two murine class II loci by inducing GVHD in donor/recipient combinations differing at the I-A, I-E, or both I-A and I-E loci. Serum autoantibody levels were mostly higher in I-E-induced GVHD, compared with I-A GVHD, and anti-Sm and anti-dsDNA were produced only in the I-E groups. When the GVHD was induced by differences at both I-A and I-E loci, autoantibody levels and specificities were generally comparable to the I-E group. Only anti-DPP-IV and IgG2bb-specific IgM rheumatoid factor were expressed at higher levels in the I-A and the I-A/E groups, but both autoantibodies were also present in the I-E group. Renal disease, in contrast to autoantibody production, was significantly greater in I-A-induced GVHD. Proteinuria was detected in both the I-A and I-A/E groups, but not in the I-E group. Histopathologic data also showed substantial glomerulonephritis in the I-A and I-A/E groups, but little in the I-E group. IgM deposits were detected in the mesangial region of all groups, but were more marked in the I-A and I-A/E groups. IgG deposits were far more prevalent in the I-A and I-A/E groups and were located predominantly in the capillary walls. These results show a direct relationship between the recognition of specific foreign Ia molecules and the autoimmunity observed: I-E resulted in elevated autoantibody production; I-A resulted in glomerulonephritis; whereas both I-A and I-E resulted in additive autoimmune manifestations. These results also showed an apparent disparity between the presence of commonly measured autoantibodies and the development of renal disease. This work provides a model to delineate further the regulatory role of the MHC class II loci in the development of autoimmunity.