Mechanisms of immune-deposit formation and the mediation of immune renal injury.
Mechanisms of immune-deposit formation and the mediation of immune renal injury.
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DOI：
10.1007/s10157-005-0357-8
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发表时间：
2005-09-01
影响因子：
2.3
通讯作者：
Couser, William G
中科院分区：
文献类型：
--
作者：
Nangaku, Masaomi;Couser, William G
预先形成的免疫复合物的被动捕获是导致某些与系膜或内皮下沉积物相关的肾小球肾炎的原因。在这些情况下，循环抗原的生化特征在确定免疫复合物的生物活性方面发挥着重要作用。循环免疫复合物疾病的例子包括兔子的经典急性和慢性血清病模型以及人类狼疮性肾炎。免疫沉积物也“原位”形成。原位免疫沉积物形成可能发生在上皮下、内皮下和系膜部位。原位免疫复合物形成最常在具有上皮下免疫沉积物的膜性肾病的海曼肾炎模型中进行研究。虽然海曼肾炎的自身抗原靶标已被确定为巨蛋白，但直到最近确定中性肽链内切酶作为靶标之一，人膜性肾病的致病性抗原靶标才为人所知。人类膜性肾病很可能不存在通用抗原。免疫复合物可以通过吸引循环炎症细胞或激活驻留肾小球细胞释放血管活性物质、细胞因子和凝血激活剂来损害肾小球结构。然而，免疫复合物介导的肾小球损伤的主要介质是补体系统，特别是C5b-9膜攻击复合物的形成。 C5b-9 以亚溶解量插入肾小球细胞膜，在那里产生细胞活化，将正常细胞转化为导致损伤的常驻炎症效应细胞。补体系统的过度激活通常通过一系列循环和细胞结合的补体调节蛋白来防止。这些蛋白质的遗传缺陷或突变可导致肾小球疾病的自发发展。人类疾病中特定抗原的鉴定可能会导致基础疗法的发展。未来特别有前途的治疗方法包括选择性免疫抑制和干扰补体激活和 C5b-9 介导的细胞损伤。
The passive trapping of preformed immune complexes is responsible for some forms of glomerulonephritis that are associated with mesangial or subendothelial deposits. The biochemical characteristics of circulating antigens play important roles in determining the biologic activity of immune complexes in these cases. Examples of circulating immune complex diseases include the classic acute and chronic serum sickness models in rabbits, and human lupus nephritis. Immune deposits also form "in situ". In situ immune deposit formation may occur at subepithelial, subendothelial, and mesangial sites. In situ immune-complex formation has been most frequently studied in the Heymann nephritis models of membranous nephropathy with subepithelial immune deposits. While the autoantigenic target in Heymann nephritis has been identified as megalin, the pathogenic antigenic target in human membranous nephropathy had been unknown until the recent identification of neutral endopeptidase as one target. It is likely that there is no universal antigen in human membranous nephropathy. Immune complexes can damage glomerular structures by attracting circulating inflammatory cells or activating resident glomerular cells to release vasoactive substances, cytokines, and activators of coagulation. However, the principal mediator of immune complex-mediated glomerular injury is the complement system, especially C5b-9 membrane attack complex formation. C5b-9 inserts in sublytic quantities into the membranes of glomerular cells, where it produces cell activation, converting normal cells into resident inflammatory effector cells that cause injury. Excessive activation of the complement system is normally prevented by a series of circulating and cell-bound complement regulatory proteins. Genetic deficiencies or mutations of these proteins can lead to the spontaneous development of glomerular disease. The identification of specific antigens in human disease may lead to the development of fundamental therapies. Particularly promising future therapeutic approaches include selective immunosuppression and interference in complement activation and C5b-9-mediated cell injury.