Molecular mechanisms of vascular injury in an autoantibody-induced model of granulomatous arteritis

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MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop immune complex-mediated glomerulonephritis, granulomatous arteritis, chronic destructive arthritis, and thrombocytopenia Recent genetic analyses in a variety of lupus-prone strains have pointed out a close correlation between autoantibodies reactive with the endogenous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. We have previously shown that a high proportion of anti-gp70 antibody-producing hybridoma clones established from MRL/lpr mice induce proliferative or wire loop-like glomerular pathology with massive granular depositions of gp70, IgG and C3 in affected glomeruli when transplanted into syngeneic non-autoimmune or severe combined immunodeficiency mice.We found here that repeated intravenous injections of purified monoclonal anti-gp70 autoantibodies induced glomerular pathology associated with gp70 deposition. Further, the above injections of the anti-gp70 antibody purified from clone 12H5.1 also induced granulomatous arteritis of the lungs in a half of the injected (BALB/c×MRL)F_1 and (C57BL/6×MRL)F_1 strains of mice.To evaluate the possible roles of Fc receptor-expressing cells and complements, common FcRγ-chain-knockout FcγRIIb-knowckout, and C3-knockout strains on the C57BL/6 background were mated with MRL mice, and F_2 progenies possessing the each homozygous knockout genotype were selected. Purified antui-gp70 monoclonal antibody 12H5.1 was injected repeatedly into the F_2 mice, and the development of granulomatous arteritis was evaluated histopathologically. The results indicated that the formation of circulating immune complexes was involved in the development of the antibody-induced arteritis.