Immune Interactions with the Mucus-Associated Microbiota

项目总结/摘要 统称为炎症性肠病（IBD）的病症的特征在于异常的肠内分泌。 对肠道菌群的免疫反应。建立和维持对暴力的容忍， 微生物群是通过细胞和分子的复杂和动态网络来实现的， 免疫反应性。阐明这些天然途径限制免疫力的机制， 通常良性的上皮细胞，特别是那些占据上皮边缘的小生境的上皮细胞， 增强我们靶向这些相互作用以预防和/或治疗肠道炎症的能力。 我们假设，高亲和力，胸腺依赖性（T依赖性）抗体反应是必不可少的， 粘液相关细菌群落的调节。T依赖性抗体反应尤其是 在宿主对肠道病原体入侵的反应中很重要。因为一些有用的水生物种 利用与病原体类似的机制在肠上皮衬里的粘液层中建立生态位， 这是理所当然的，类似的免疫机制被用来控制这些生物体。我们发现 用最小的粘液相关聚生体定殖的小鼠显示出主要依赖于T的IgG， 反应此外，T依赖性抗体产生受损的小鼠显著减少了 对来源于粘液相关细菌的抗原的总抗体应答，包括特异性鞭毛蛋白 来源于毛螺菌科的成员。粘液相关细菌定植，或 T依赖性抗体的缺乏，在这种生物体的存在下，与增加的生产相一致 免疫调节细胞因子白细胞介素-10（IL-10）通过大肠中的CD 4 T细胞。因此，委员会认为， 这两种途径的同时破坏导致自发性结肠炎症。在本提案中，我们 将利用确定的微生物和它们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相互作用促进了对这些 社区.此外，我们还将探索T依赖性抗人IgG 1在免疫应答中的新作用。 免疫稳态的建立和维持。如果成功的话，我们的研究将确定 由此TD抗结肠癌抗体促进结肠上皮边缘的免疫正常化， 不断地减轻对粘液相关细菌的多样性群落的有害反应性的风险。

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.