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过表达 BAFF 的小鼠出现共生菌群依赖、IgA 相关的肾炎。

Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy.

机构信息

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

出版信息

J Clin Invest. 2011 Oct;121(10):3991-4002. doi: 10.1172/JCI45563. Epub 2011 Sep 1.

Abstract

B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

摘要

B 细胞激活因子肿瘤坏死因子家族(BAFF)是一种有效的 B 细胞存活因子。过表达 BAFF 的转基因小鼠(BAFF-Tg 小鼠)表现出自身免疫疾病的特征,包括 B 细胞增生和高免疫球蛋白血症,并随着年龄的增长发展为致命的肾炎。然而,基础血清 IgA 水平也升高,这表明这些小鼠的病理可能比最初认为的更为复杂。与这一观点一致,我们在这里证明,BAFF-Tg 小鼠有 IgA 的系膜沉积,以及循环中高分子量 IgA 的异常糖基化。BAFF-Tg 小鼠的肾脏疾病与 IgA 有关,因为肾炎小鼠和 IgA 基因缺失的 BAFF-Tg 小鼠的血清 IgA 水平显著升高。共生菌群的存在对于升高的血清 IgA 表型是必不可少的,而且出乎意料的是,在血液中发现了与共生细菌反应的 IgA 抗体。这些数据说明了过量的 B 细胞存活信号如何扰乱了与微生物群的正常平衡,导致正常黏膜-外周区室化的破坏。这种破坏可能使非黏膜系统容易发生某些免疫疾病。事实上,我们发现,一部分 IgA 肾病患者的血清中有增殖诱导配体(APRIL)水平升高,APRIL 是一种与 BAFF 相关的细胞因子。BAFF-Tg 小鼠和人类 IgA 肾病之间的这些相似之处可能为探索黏膜环境与肾脏病理之间的联系提供了一个新的框架。

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