Roles of endogenous retroviruses and platelets in the development of vascular injury in spontaneous mouse models of autoimmune diseases

MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop immune complex-mediated glomerulonephritis, granulomatous arteritis, and thrombocytopenia. Recent genetic analyses in a few different strains of lupus-prone mice 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 also shown that autoantibodies reactive with endogenous retroviral gp70 are closely correlated with the development of necrotizing polyarteritis in another lupus-prone strain of mice, SL/Ni. However, suggested pathogenicity of anti-gp70 autoantibodies has not yet been directly tested. To examine if anti-gp70 autoantibodies induce glomerular and vascular pathology, we established from unmanipulated MRL/lpr mice hybridoma clones that secrete monoclonal antibodies reactive with endogenous xenotropic viral env gene products. As reported separately, a high proportion of these anti-gp70 antibody-producing hybridoma clones induced in syngeneic non-autoimmune and severe combined immunodeficiency mice proliferative or wire loop-like glomerular lesions with granular deposits of gp70, IgG, and C3 in affected glomeruli. Some mice transplanted with these anti-gp70 autoantibody-producing hybridoma cells also showed massive subendothelial deposition of electron-dense materials in small arterioles in the kidneys. Furthermore, we identified an IgG2a-producing anti-gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and amenia upon transplantation into syngeneic non-autoimmune mice. This anti-gp70 autoantibody bound onto the surfaces of mouse platelets, and specifically precipitated a platelet protein with an approximate relative molecular mass of 40 000. Attachment of activated platelets to the intimal surfaces of small arteries was also observed by electron microscopy in mice transplanted with the pathogenic anti-gp70 IgG2a-producing hybridoma cells, suggesting an interaction between antibody-bound platelets and endothelial cells.