Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy
Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy
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DOI：
10.1172/jci45563
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Browning, Jeffrey L.
中科院分区：
文献类型：
--
作者：
McCarthy, Douglas D.;Kujawa, Julie;Browning, Jeffrey L.
TNF家族的B细胞活化因子（BAFF）是有效的B细胞存活因子。BAFF过表达转基因小鼠（BAFF-Tg小鼠）表现出自身免疫性疾病的特征，包括B细胞增生和高丙种球蛋白血症，并随着年龄的增长发展为致命性肾炎。然而，基础血清伊加水平也升高，表明这些小鼠的病理可能比最初认识到的更复杂。与此一致，我们在此证明BAFF-Tg小鼠具有伊加的系膜沉积物沿着高循环水平的异常糖基化的聚合伊加。BAFF-Tg小鼠的肾脏疾病与伊加相关，因为在肾炎小鼠中血清伊加高度升高，并且伊加基因缺失的BAFF-Tg小鼠表现出较少的肾脏病理。肠道植物群的存在是血清伊加表型升高所必需的，并且出乎意料地，在血液中发现肠道细菌反应性伊加抗体。这些数据说明了过量的B细胞存活信号传导如何扰乱与微生物群的正常平衡，导致正常粘膜-外周区室化的破坏。这种破坏可能使非粘膜系统易患某些免疫疾病。事实上，我们发现一部分伊加肾病患者血清中增殖诱导配体（APRIL）水平升高，APRIL是一种与BAFF相关的细胞因子。BAFF-Tg小鼠和人类伊加肾病之间的这些相似之处可能提供一个新的框架，探索粘膜环境和肾脏病理之间的联系。
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 hyper-gammaglobulinemia, 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.