Chronic graft versus host disease-associated autoimmune manifestations are independently regulated by different MHC class II loci.

Abstract

Abstract 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.