Immunometabolism of IgA-Microbiota Interaction in Gut Homeostasis and Inflammation

共生微生物区系与肠道免疫建立了一种互惠关系。 通过T细胞依赖(TD)和T细胞非依赖(TI)激活B细胞的系统 产生高亲和力和低亲和力的分泌型免疫球蛋白A的途径 分别用于抗原。高亲和力(HA)-SIgA从相对较好的- 了解涉及CD40L的TD途径，通常被认为是肠道必需的 由于其对细菌细胞的特殊识别而产生的动态平衡。然而，最近的研究 也特别表明(LA)-SIgA来自一个知之甚少的TI途径 识别共生菌。更多证据表明，HA-SIGA外衣 炎症性肠病(IBD)患者中的结肠菌群增加 肠道动态平衡可能需要平衡的HA-SIGA和LA-SIGA反应。 该提案将结合对原发免疫缺陷(PID)的深入分析 研究基因敲除、无菌和诺生菌小鼠模型的标本进行解剖 LA-SIGA和HA-SIGA应答的调节、微生物区系反应性和功能。 初步数据显示，LA-SIgA的TI产生涉及CD40非依赖性 BAFF/APRIL受体TACI对肠道B细胞的激活作用 通过激酶mTOR进行切换。更多的初步证据表明，TACI 缺乏通过减少涂层而损害微生物区系多样性和肠道动态平衡 用LA-SIGA对细菌细胞进行了鉴定。在这里，我们假设TACI和CD40是 MTOR调节的TI和TD通路对LA-SIgA和HA-SIgA的应答 目标是非重叠的肠道细菌群。提出了三个具体目标。 目的1阐明TACI和TACI对LA-SIgA和HA-SIgA应答的调节作用 CD40，并分析它们对肠道微生物区系的反应性。目标2是描述 LA-SIGA和HA-SIGA靶向细菌群落的组成和功能 抗体；目标3是剖析LA-SIgA和HA-SIgA的功能相互作用 TACI和CD40对mTOR产生的B细胞信号的应答这种激活剂 通过参与TACI至MyD88激活B细胞。建议的研究(项目3) 将利用该联盟提供的细胞、粪便和组织 Cunningham-Rundles小组的补充和综合专门知识，该小组 评估TACI在B细胞增殖和分化中的作用(项目1)， Meffre小组(项目2)，探索TACI和其他关键抗体的作用- B细胞耐受性的调节分子，以及卡萨诺瓦小组(项目4)，这 寻求在PID中识别新的致病基因。

The commensal microbiota establishes a mutualistic relationship with the gut immune system by activating B cells via T cell-dependent (TD) and T cell-independent (TI) pathways that generate secretory immunoglobulin A (SIgA) with high and low affinity for antigen, respectively. High-affinity (HA)-SIgA emerges from a relatively well- understood TD pathway involving CD40L and is generally viewed as essential for gut homeostasis due to its specific recognition of bacterial cells. However, recent studies indicate that also (LA)-SIgA from a poorly understood TI pathway specifically recognizes commensal bacteria. Additional evidence shows that HA-SIgA coats colitogenic bacteria in patients with inflammatory bowel disease (IBD), raising the possibility that gut homeostasis requires balanced HA-SIgA and LA-SIgA responses. This proposal will combine an in-depth analysis of primary immunodeficiency (PID) specimens with studies of knockout, germfree and gnotobiotic mouse models to dissect the regulation, microbiota reactivity and function of LA-SIgA and HA-SIgA responses. Preliminary data show that TI production of LA-SIgA involves CD40-independent activation of gut B cells by TACI, a BAFF/APRIL receptor that triggers IgM-to-IgA class switching through the kinase mTOR. Additional preliminary evidence shows that TACI deficiency impairs microbiota diversity and gut homeostasis by decreasing the coating of bacterial cells by LA-SIgA. Here, we hypothesize that TACI and CD40 orchestrate LA-SIgA and HA-SIgA responses through mTOR-regulated TI and TD pathways targeting non-overlapping consortia of gut bacteria. Three specific aims are proposed. Aim 1 is to elucidate the regulation of LA-SIgA and HA-SIgA responses by TACI and CD40 and dissect their reactivity for the gut microbiota. Aim 2 is to characterize the composition and function of bacterial communities targeted by LA-SIgA and HA-SIgA antibodies; Aim 3 is to dissect the functional interplay of LA-SIgA and HA-SIgA responses induced by TACI and CD40 with B cell signals from mTOR. This kinase activates B cells by engaging TACI through MyD88. The proposed studies (Project 3) will take advantage of cells, stool and tissues made available by this consortium and of the complementary and integrative expertise of the Cunningham-Rundles group, which evaluates the role of TACI in B cell proliferation and differentiation (Project 1), the Meffre group (Project 2), which explores the role of TACI and other key antibody- regulating molecules in B cell tolerance, and the Casanova group (Project 4), which seeks to identify new causative genes in PIDs.