PATHOPHYSIOLOGICAL ANALYSIS OF GOODPASTURE SYNDROME USING FcRγ-DEFICIENT MICE

最近的几项研究表明，铁受体（FcR）而不是补体系统在引发包括Goodpasture综合征在内的超敏反应中的核心作用。我们利用抗肾小球基底膜（GBM）抗体介导的加速型肾小球肾炎和肺泡炎（II型超敏性疾病的代表）小鼠模型，研究了FcR对IgG （FcγR）的作用。正常兔IgG预免疫后静脉注射兔抗gbm抗体诱导野生型C57BL/6和CD40 +/-小鼠出现蛋白尿和氮质血症，而ferr γ链(FcRγ) -/-小鼠和CD40 -/-小鼠无此反应。光镜下可见野生型C57BL/6和CD40 +/-小鼠肾小球明显的组织损伤。然而，FcRγ -/-小鼠肾小球除多形核细胞浸润外，未见其他组织损伤。CD40 -/-小鼠肾小球基本正常。免疫组化显示兔IgG与GBM结合。然而，在CD40 -/-小鼠中未观察到小鼠IgG和补体沉积到肾小球，在FcRγ -/-或CD40 -/-小鼠中未观察到纤维蛋白沉积。此外，抗基底膜抗体介导的肺泡炎在FcRγ -/-小鼠中未被诱导。这些发现提示fc - γ r可能引发抗基底膜抗体介导的肾脏和肺部疾病，即Goodpasture综合征。我们得出结论，FcγR而不是补体系统在II型超敏性疾病的发展中起关键作用。

Several recent studies have demonstrated the central role of Fe receptor (FcR) rather than the complement system in triggering hypersensitivity reactions including Goodpasture syndrome. We investigated the role of FcR for IgG (FcγR) using a murine model of accelerated anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis and alveolitis as a representative of type II hypersensitivity diseases. Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40 +/- mice but not in FeR γ chain (FcRγ) -/- mice, or CD40 -/- mice. Light microscope findings revealed marked tissue damage in the glomeruli of wild-type C57BL/6 and CD40 +/- mice. However, no tissue damage except polymorphonuclear cell infiltration was observed in the glomeruli of FcRγ -/- mice. The glomeruli of CD40 -/- mice were almost normal. Immunohistochemistry revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM antibody. However, depositions of mouse IgG and complement to the glomeruli were not observed in CD40 -/- mice, and deposition of fibrin was not observed in FcRγ -/-or CD40 -/- mice. Furthermore, anti-basement membrane antibody-mediated alveolitis was not induced in FcRγ -/- mice. These findings suggest that FcγR may initiate anti-basement membrane antibody-mediated renal and pulmonary disease, that is named as Goodpasture syndrome. We conclude that FcγR rather than the complement system is critically involved in the development of type II hypersensitivity diseases.