Suzuki Y, Shirato I, Okumura K, Ravetch J V, Takai T, Tomino Y, Ra C
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Kidney Int. 1998 Oct;54(4):1166-74. doi: 10.1046/j.1523-1755.1998.00108.x.
The contribution of antibody and/or immune-complex to the pathogenesis of immunologically-mediated glomerulonephritis is not fully understood, although it has been recently clarified that Fc receptors (FcRs) play critical roles in the inflammatory cascade. We therefore re-evaluated the classical model of glomerulonephritis, anti-glomerular basement membrane antibody-induced glomerulonephritis (Anti-GBM GN), from the standpoint of FcRs and also investigated the residual FcR-independent mechanisms.
We adopted an Anti-GBM GN mouse model that has two strains deficient in the FcR gamma chain [gamma(-/-)] or Fc gammaRIIB [RII(-/-)], and analyzed functional (urinary protein, serum creatinine, BUN) and pathological changes of the glomeruli. For the analyses of FcR-independent mechanisms, several doses of nephrotoxic serum were applied, and then mice were treated either with cobra venom factor or an angiotensin II type 1 receptor antagonist in gamma(-/-) mice.
In gamma(-/-) mice, renal injuries were dramatically attenuated with an absence of polymorphonuclear cell (PMN) influx, while RII(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. In the absence of FcR-dependent effects in gamma(-/-) mice, the FcR-independent pathway lead to chronic renal damage characterized by mesangial proliferation and progressive expansion of mesangial area, with monocyte/macrophage accumulation and with the expression of alpha smooth muscle actin in the mesangial cells and interstitium. Those injuries in gamma(-/-) mice were not attenuated by the decomplementation, but completely abolished by using an angiotensin II type 1 receptor antagonist.
Our results clearly demonstrate that FcRs play a pivotal role in Anti-GBM GN, especially in its acute phase. We further clarified the existence of FcR and complement-independent but antibody-dependent pathway. Furthermore, we found that those pathological changes were strongly related to the renin-angiotensin system.
尽管最近已明确Fc受体（FcRs）在炎症级联反应中起关键作用，但抗体和/或免疫复合物在免疫介导的肾小球肾炎发病机制中的作用尚未完全阐明。因此，我们从FcRs的角度重新评估了肾小球肾炎的经典模型，即抗肾小球基底膜抗体诱导的肾小球肾炎（抗GBM GN），并研究了残留的不依赖FcR的机制。
我们采用了一种抗GBM GN小鼠模型，该模型有两种缺乏FcRγ链[γ(-/-)]或FcγRIIB [RII(-/-)]的品系，并分析了肾小球的功能（尿蛋白、血清肌酐、血尿素氮）和病理变化。为了分析不依赖FcR的机制，应用了几种剂量的肾毒性血清，然后在γ(-/-)小鼠中用眼镜蛇毒因子或血管紧张素II 1型受体拮抗剂进行治疗。
在γ(-/-)小鼠中，肾损伤明显减轻，多形核细胞（PMN）浸润缺失，而RII(-/-)小鼠尽管PMN浸润正常，但肾小球损伤加速。在γ(-/-)小鼠中，在不存在FcR依赖性效应的情况下，不依赖FcR的途径导致以系膜增生和系膜面积逐渐扩大为特征的慢性肾损伤，伴有单核细胞/巨噬细胞积聚以及系膜细胞和间质中α平滑肌肌动蛋白的表达。γ(-/-)小鼠的这些损伤未因补体灭活而减轻，但使用血管紧张素II 1型受体拮抗剂可完全消除。
我们的结果清楚地表明，FcRs在抗GBM GN中起关键作用，尤其是在急性期。我们进一步阐明了存在不依赖FcR和补体但依赖抗体的途径。此外，我们发现这些病理变化与肾素-血管紧张素系统密切相关。
