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

MRL/MpJ-lpr/lpr （MRL/lpr）小鼠可自发发生免疫复合物介导的肾小球肾炎、肉芽肿性动脉炎、慢性破坏性关节炎和血小板减少症。最近对多种狼疮易感菌株的遗传分析指出，与内源性逆转录病毒env基因产物gp70反应的自身抗体与肾小球肾炎的发展和严重程度密切相关。我们之前的研究表明，在MRL/lpr小鼠中建立的高比例抗gp70抗体产生杂交瘤克隆，在移植到同基因非自身免疫性或严重联合免疫缺陷小鼠时，可诱导增生或丝环样肾小球病理，病变肾小球中有大量gp70、IgG和C3颗粒沉积。我们发现反复静脉注射纯化的单克隆抗gp70自身抗体可诱导与gp70沉积相关的肾小球病理。此外，上述从克隆12H5.1纯化的抗gp70抗体的注射也诱导了一半的注射小鼠（BALB/c×MRL）F_1和（C57BL/6×MRL）F_1的肺部肉芽肿性动脉炎。为了评估Fc受体表达细胞和补体的可能作用，将常见的fcr γ链敲除株Fcγ riib敲除株和C57BL/6背景下的c3敲除株与MRL小鼠进行配对，并选择具有各纯合敲除基因型的F_2后代。用纯化的抗gp70单克隆抗体12H5.1反复注射F_2小鼠，对肉芽肿性动脉炎的发生进行组织病理学观察。结果表明，循环免疫复合物的形成参与了抗体性动脉炎的发生。

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.