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古德巴德综合征在内的超敏反应中起着中心作用。以加速型抗肾小球基底膜抗体介导的肾小球肾炎和肺泡炎作为II型变态反应性疾病的代表动物模型，研究FcR对Ig G(FcγR)的作用。用正常兔免疫球蛋白预免后静脉注射兔抗γ抗体，可引起野生型C57BL/6和CD40+/-小鼠蛋白尿和氮质血症，但对FER-γ-/-小鼠和CD40-/-小鼠无影响。光镜下可见野生型C57BL/6和CD40+/-小鼠肾小球组织损伤明显。而FCRγ-/-鼠肾小球内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。免疫组织化学结果显示，在所有注射抗GBM抗体的小鼠中，兔免疫球蛋白与GBM结合。然而，在CD40-/-小鼠中没有观察到小鼠免疫球蛋白和肾小球补体的沉积，在fcrγ-/-或CD40-/-小鼠中也没有观察到纤维蛋白的沉积。此外，抗基底膜抗体介导的肺泡炎在FCRγ-/-小鼠中未被诱导。这些结果提示，FcγR可能启动了抗基底膜抗体介导的肾和肺疾病，被称为古巴斯普雷综合征。我们得出结论，FcγR而不是补体系统在II型变态反应性疾病的发生中起关键作用。

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.