Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-α production
Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-α production
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DOI：
10.4049/jimmunol.176.1.632
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Mohan, C
中科院分区：
文献类型：
--
作者：
Fu, YY;Xie, C;Mohan, C
先天刺激被广泛认为是全身免疫反应的佐剂。然而，它们在导致终末器官疾病中的作用尚不清楚。单独针对肾小球的抗体的被动转移会引发轻微的肾脏疾病，而先天刺激的同时传递则会引发严重的肾炎，其特征是伴有新月体形成的增殖性肾小球肾炎和肾小管间质疾病。具体来说，分别使用肽聚糖、聚(I:C)、LPS和鞭毛蛋白刺激TLR2、TLR3、TLR4和TLR5，都可以促进抗肾小球Ab诱发的肾炎。在该模型中，先天性和免疫触发因素协同激活了多种细胞因子和趋化因子，包括 IL-1、IL-6、TNF-α 和 MCP-1，其中一些被证明对于肾脏疾病的发展至关重要。遗传学研究表明，先天触发因素依赖于 TLR/IL-1R 相关激酶介导的信号传导，而免疫成分则取决于 FcR 介导的信号传导。重要的是，浸润白细胞以及内在肾小球细胞都可能有助于整合这些不同的信号。推断自发性免疫介导的肾炎，尽管适应性免疫系统在产生终末器官靶向抗体方面可能很重要，但这些抗体造成的损害程度可能在很大程度上取决于先天免疫系统的提示。
Innate stimuli are well recognized as adjuvants of the systemic immune response. However, their role in driving end-organ disease is less well understood. Whereas the passive transfer of glomerular-targeting Abs alone elicited minimal renal disease, the concomitant delivery of innate stimuli triggered severe nephritis, characterized by proliferative glomerulonephritis with crescent formation, and tubulointerstitial disease. Specifically, stimulating TLR2, TLR3, TLR4, and TLR5 by using peptidoglycan, poly(I: C), LPS, and flagellin, respectively, all could facilitate anti-glomerular Ab-elicited nephritis. In this model, innate and immune triggers synergistically activated several cytokines and chemokines, including IL-1, IL-6, TNF-alpha, and MCP-1, some of which were demonstrated to be absolutely essential for the development of renal disease. Genetic studies revealed that, whereas the innate trigger is dependent on TLR/IL-1R-associated kinase-mediated signaling, the immune component was contingent on FcR-mediated signals. Importantly, infiltrating leukocytes as well as intrinsic glomerular cells may both serve to integrate these diverse signals. Extrapolating to spontaneous immune-mediated nephritis, although the adaptive immune system may be important in generating end-organ targeting Abs, the extent of damage inflicted by these Abs may be heavily dependent on cues from the innate immune system.