CHRONIC CRAFT VERSUS HOST DISEASE-ASSOCIATED AUTOIMMUNE MANIFESTATIONS ARE INDEPENDENTLY REGULATED BY DIFFERENT MHC CLASS-II LOCI

Murine chronic graft vs host disease (GVHD) resembles human SLE in aut oantibody specificities and glomerulonephritis. Chronic GVHD is induce d by donor T cell recognition of recipient la Ag. This study compared the role of the two murine class II loci by inducing GVHD in donor/rec ipient combinations differing at the I-A, I-E, or both I-A and I-E loc i. Serum autoantibody levels were mostly higher in I-E-induced GVHD, c ompared with I-A GVHD, and anti-Sm and anti-dsDNA were produced only i n 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 co mparable to the I-E group. Only anti-DPP-IV and IgG2b(b)-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 grou p. Renal disease, in contrast to autoantibody production, was signific antly greater in I-A-induced GVHD. Proteinuria was detected in both th e 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 group s, but little in the I-E group. IgM deposits were detected in the mesa ngial 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 grou ps and were located predominantly in the capillary walls. These result s show a direct relationship between the recognition of specific forei gn la molecules and the autoimmunity observed: I-E resulted in elevate d autoantibody production; I-A resulted in glomerulonephritis; whereas both I-A and I-E resulted in additive autoimmune manifestations. Thes e results also showed an apparent disparity between the presence of co mmonly measured autoantibodies and the development of renal disease. T his work provides a model to delineate further the regulatory role of the MHC class II loci in the development of autoimmunity.