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-mediate d glomerulonephritis, granulomatous arteritis, and thrombocytopenia. Recent genetic analyses in a few different strains of lupus-prone mice have point ed out a close correlation between autoantibodies reactive with the endogen ous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. We have also shown that autoantibodies reactive with en dogenous retroviral gp70 are closely correlated with the development of nec rotizing polyarteritis in another lupus-prone strain of mice, SL/Ni. Howeve r, suggested pathogenicity of anti-gp70 autoantibodies has not yet been dir ectly tested. To examine if anti-gp70 autoantibodies induce glomerular and vascular pathology, we established from unmanipulated MRL/lpr mice hybridom a clones that secrete monoclonal antibodies reactive with endogenous xenotr opic viral env gene products. As reported separately, a high proportion of these anti-gp70 antibody-producing hybridoma clones induced in syngeneic no n-autoimmune and severe combined immunodeficiency mice proliferative or wir e loop-like glomerular lesions with granular deposits of gp70, IgG, and C3 in affected glomeruli. Some mice transplanted with these anti-gp70 autoanti body-producing hybridoma cells also showed massive subendothelial depositio n of electron-dense materials in small arterioles in the kidneys. Furthermo re, we identified an IgG2a-producing anti-gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and ame nia 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 sm all arteries was also observed by electron microscopy in mice transplanted with the pathogenic anti-gp70 IgG2a-producing hybridoma cells, suggesting a n interaction between antibody-bound platelets and endothelial cells. (C) 2 000 Elsevier Science Ireland Ltd. All rights reserved.