Cellular and molecular mechanisms regulating immunoglobulin A production

胃肠道(GI)是哺乳动物身体最大的粘膜表面，大量寄生着通常无害的微生物。建立和维持肠道微生物区系和密集分布在胃肠道的淋巴细胞之间的动态平衡所需的一个关键机制是产生和跨上皮运输多反应性免疫球蛋白(Ig)A。在粘膜组织中，B细胞对细胞因子做出反应，通常在没有T细胞帮助的情况下，经历Ig受体到IgA的类切换重组(CSR)，并分化为浆细胞(PC)。我们最近的观察表明，肠道分泌IgA的PC已经具备了产生抗微生物介质TNFa和iNOS的能力，并表达了许多与单核/粒细胞类型有关的分子。这些额外的属性对于应对胃肠道中巨大的细菌负荷是必不可少的，因为B系细胞中TNFa和iNOS的缺失导致肠道微生物区系的变化和肠道嗜肠病原体的清除不良。这些发现揭示了一种新的适应，以维持肠道内的动态平衡，并扩大了一些B细胞所表现出的保护性反应的谱系。为了进一步破译iNOS和TNFa调控的分子通路，本研究将专门探讨iNOS和TNF？的作用。在下列情况下用于IgA PC细胞的发育。(I)我们假设iNOS和肿瘤坏死因子？在调节原蛋白转换酶Furin以及BAFF和APRIL的功能中发挥核心作用，从而指导后续的IgA CSR。(Ii)我们假设iNOS和肿瘤坏死因子？在调节粘膜B细胞的TACI功能中发挥核心作用，从而指导后续的IgA CSR。概述的研究计划勾勒出了关于IgA CSR所需的分子和细胞机制的两个关键问题，所获得的知识将对我们理解如何建立和维持与共生微生物群的动态平衡至关重要。

The gastrointestinal (GI) tract is the largest mucosal surface of the mammalian body and is heavily colonized by normally harmless microbes. A key mechanism required for establishing and maintaining a homeostatic balance between the intestinal microbiota and the lymphocytes that densely populate the GI tract is the production and trans-epithelial transport of poly-reactive Immunoglobulin (Ig) A. Within the mucosal tissues, B cells respond to cytokines, often in the absence of T cell help, undergo class switch recombination (CSR) of their Ig receptor to IgA, and differentiate to become plasma cells (PC). Our recent observations demonstrate that intestinal IgA+-secreting PC have acquired the ability to produce the anti-microbial mediators TNFa and iNOS and express many molecules that are commonly associated with monocyte/granulocytic cell types. These additional attributes are essential for coping with the tremendous bacterial load in the GI tract, since the deletion of TNFa and iNOS in B-lineage cells resulted in altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B lineage cells. To further decipher the molecular pathways regulated by iNOS and TNFa this research program will specifically explore the role of iNOS and TNF? for IgA+ PC cell development in the following contexts. (i) We hypothesize that iNOS and TNF? play a central role in regulating the function of the proprotein convertase furin as well as BAFF and APRIL, thereby instructing subsequent IgA CSR. (ii) We hypothesize that iNOS and TNF? play a central role in regulating the function of the TACI on mucosal B cells, thereby instructing subsequent IgA CSR. The outlined research program delineates two critical questions regarding the molecular and cellular mechanisms required for IgA CSR and the gained knowledge will be of utmost importance for our understanding of how we establish and maintain a homeostatic balance with our commensal microbiota.