Mathern Douglas R, Heeger Peter S
Translational Transplant Research Center, Department of Medicine, Recanati Miller Transplant Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Translational Transplant Research Center, Department of Medicine, Recanati Miller Transplant Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
Clin J Am Soc Nephrol. 2015 Sep 4;10(9):1636-50. doi: 10.2215/CJN.06230614. Epub 2015 Jan 7.
The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.
补体级联反应，传统上被认为是宿主抵御病原体所需的固有免疫效应臂，现在被认为是各种肾脏疾病的关键致病介质。由肝脏产生并在血浆中循环的补体成分通过经典和/或甘露糖结合凝集素途径被激活，以介导抗HLA抗体引发的肾移植排斥反应和自身抗体引发的肾小球肾炎，后者包括膜性肾小球病、抗肾小球基底膜病和狼疮性肾炎。补体调节因子的遗传性和/或获得性异常，必然会限制对替代途径补体激活的抑制，从而导致C3肾病和非典型溶血尿毒综合征的发病机制。越来越多的证据表明，内皮细胞和/或肾小管细胞产生的补体与肾脏缺血再灌注损伤和进行性肾脏纤维化的发病机制有关。自21世纪中期以来出现的数据还表明，包括T细胞和抗原呈递细胞在内的免疫细胞在同源相互作用过程中产生替代途径补体成分。随后的局部补体激活产生过敏毒素C3a和C5a，它们与双方各自的受体（C3aR和C5aR）结合，以增强效应T细胞的增殖和存活，同时抑制调节性T细胞的诱导和功能。这种免疫细胞衍生的补体增强了致病性同种异体反应性T细胞免疫，导致移植排斥反应，并可能促成其他T细胞介导的肾脏疾病的发病机制。此外，在抗中性粒细胞胞浆抗体介导的肾血管炎模型中，已证明中性粒细胞上的C5a/C5aR连接有助于血管炎症。新的转化免疫学研究以及阻断人类补体成分和受体的药物的开发，现在允许测试一个有趣的概念，即针对各种肾脏疾病患者的补体有可能消除疾病进展并改善患者健康。
