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，通常由无害的微生物大量定植。建立和维持肠道微生物群和密集分布在胃肠道中的淋巴细胞之间的稳态平衡所需的关键机制是多反应性免疫球蛋白（IG）A的产生和跨上皮转运。在粘膜组织内，B细胞通常在没有T细胞帮助的情况下响应于细胞因子，经历其IG受体到伊加的类别转换重组（CSR），并分化成浆细胞（PC）。我们最近的观察表明，肠道伊加+分泌PC已经获得了产生抗微生物介质TNF α和iNOS的能力，并表达许多通常与单核细胞/粒细胞类型相关的分子。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群的多样化改变和肠道嗜性病原体的清除不良。这些发现揭示了维持肠道内稳态的新适应，并扩展了一些B谱系细胞所表现出的保护性反应的全部功能。为了进一步破译由iNOS和TNF α调节的分子通路，本研究计划将专门探讨iNOS和TNF？伊加+ PC细胞在以下情况下的发育。(i)我们推测，iNOS和TNF？在调节前蛋白转化酶弗林蛋白酶以及BAFF和APRIL的功能中发挥核心作用，从而指导随后的伊加CSR。(ii)我们推测，iNOS和TNF？在调节TACI对粘膜B细胞的功能中起核心作用，从而指导随后的伊加CSR。概述的研究计划描绘了关于伊加CSR所需的分子和细胞机制的两个关键问题，并且所获得的知识对于我们了解我们如何建立和维持体内微生物群的稳态平衡至关重要。

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.