Immune Interactions with the Mucus-Associated Microbiota

项目摘要/摘要 这些疾病统称为炎症性肠病(IBD)，其特征是异常 对共生微生物群的免疫反应。建立和维持对人的容忍 微生物区系是通过复杂而动态的细胞和分子网络完成的，这些细胞和分子共同保持稳定 丧失免疫反应性。阐明这些自然途径限制免疫力的机制 正常的良性共生，特别是那些占据上皮边界的共生，最终将 提高我们针对这些相互作用预防和/或治疗肠道炎症的能力。 我们假设高亲和力、胸腺依赖(T依赖)的抗体反应对于 粘液相关细菌群落的调节。依赖T细胞的抗体反应尤其是 在宿主对肠道病原性入侵的反应中很重要。因为一些有益的共生物种 利用与病原体相似的机制在衬里肠道上皮的粘液层中建立一个生态位， 顺理成章地，类似的免疫机制也被部署来控制这些有机体。我们发现了 用最小的粘液相关联合体定植的小鼠表现出主要依赖T的免疫球蛋白G 回应。此外，T依赖抗体产生受损的小鼠显著减少 对粘液相关细菌抗原(包括特定鞭毛)的总抗体反应 来源于马鞭草科的成员。粘液相关细菌的定植，或 在这种生物存在的情况下，T依赖抗体的缺乏与产量的增加相一致 免疫调节细胞因子白介素10(IL-10)在大肠CD4T细胞中的表达。因此， 这两条通路同时中断会导致自发性结肠炎。在这项提案中，我们 将利用定义的微生物及其产生的抗原来阐明相互作用的机制 鞭毛粘液相关细菌和肠道免疫系统之间的关系促进对这些细菌的耐受 社区。此外，我们还将探索T依赖的反共生免疫球蛋白1在 建立和维持免疫动态平衡。如果成功，我们的研究将确定这些机制 由此TD抗共生抗体促进结肠上皮边界的免疫正常和 不断降低粘液相关细菌多样性群落的有害反应风险。

PROJECT SUMMARY/ABSTRACT The disorders collectively referred to as inflammatory bowel disease (IBD) are characterized by aberrant immune responses to the commensal microbiota. The establishment and maintenance of tolerance to the microbiota is accomplished via a complex and dynamic network of cells and molecules that collectively stave off immune reactivity. Elucidation of the mechanisms whereby these natural pathways limit immunity to normally benign commensals, especially those that occupy niches at the epithelial border, will ultimately enhance our ability to target these interactions for the prevention and/or treatment of intestinal inflammation. We hypothesize that high-affinity, thymus-dependent (T-dependent) antibody responses are essential for the regulation of mucus-associated bacterial communities. T-dependent antibody responses are especially important in the host response to pathogenic invasion of the gut. Since some helpful commensal species utilize similar mechanisms as pathogens to establish a niche in the mucus layer lining the intestinal epithelium, it stands to reason that similar immune mechanisms are deployed to control these organisms. We have found that mice colonized with a minimal mucus-associated consortium display a predominantly T-dependent IgG response. Moreover, mice with impaired production of T-dependent antibodies have significantly diminished total antibody responses to antigens derived from mucus-associated bacteria including specific flagellins derived from members of the family Lachnospiraceae. Colonization with mucus-associated bacteria, or the deficiency of T-dependent antibodies in the presence of such organisms, coincides with increased production of the immunoregulatory cytokine interleukin-10 (IL-10) by CD4 T cells in the large intestine. Accordingly, simultaneous disruption of these 2 pathways results in spontaneous colonic inflammation. In this proposal, we will utilize defined microbes and the antigens they generate to elucidate the mechanisms whereby interactions between flagellated mucus-associated bacteria and the gut immune system promote tolerance of these communities. In addition, we will explore novel roles for T-dependent anti-commensal IgG1 in the establishment and maintenance of immune homeostasis. If successful, our studies will define the mechanisms whereby TD anti-commensal antibodies promote immune normalcy at the colonic epithelial border and constantly mitigate the risk of deleterious reactivity to the diverse community of mucus-associated bacteria.