Mechanisms Regulating Innate Immune Responses

项目总结/摘要 宿主与微生物之间的相互作用在粘膜表面至关重要。的失调 这些相互作用可导致肠道炎症性疾病，例如炎症性肠病， （IBD）。对微生物的识别和反应最初是由模式识别受体介导的 （PRR）。PRR反应导致细胞因子分泌和细胞活化，以及微生物增殖。 间隙这些结果之间的平衡影响炎症之间的易感性。 疾病和传染病。我们的长期目标是了解IBD的介导机制， 因此，本发明提供了一种治疗IBD的方法，该方法可以改善IBD的发病机制，从而最终改善人IBD的管理和治疗。 IRF 5区域的多态性与多种免疫介导的疾病相关， 包括IBD。我们发现，IRF 5是一个最重要的遗传决定因素， 不同地区骨髓源性细胞中PRR启动的信号传导和细胞因子的个体差异 IRF 5疾病风险多态性的携带者分泌高水平的细胞因子， 对一系列PRR刺激的反应。尽管IRF 5在调节个体间 人骨髓源性PRR诱导的细胞因子的变异，IRF 5如何促进IBD 体内发病机制尚未研究（SA IC&IIC）。IBD发病机制的关键是 骨髓细胞清除微生物;然而，IRF 5如何调节居民和 致病性肠道微生物是未知的（SA III）。多个细胞亚群可以促进肠道 免疫失调和IRF 5-/-小鼠中有限的体内研究也证明了 IRF 5在T细胞结局中的作用，在狼疮模型系统中具有降低的Th 1分化。但是，在这方面， IRF 5是以T细胞内源性（SA I）还是T细胞外源性（SA II）方式调节T细胞结果， 未知，包括肠组织。我们假设IRF 5将有助于多个 免疫细胞在体内肠道免疫稳态中起重要作用， 骨髓和T细胞亚群，虽然它可能有助于结肠炎的炎症结果， 对调节肠道病原体至关重要。我们进一步假设IRF 5 IBD相关 多态性将调节IRF 5在这些相关免疫结果中的鉴定作用。我们 将整合原代人类细胞研究和小鼠体内研究，以剖析IRF 5的贡献 IBD发病机制

Project Summary/Abstract The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in the IRF5 region are associated with a wide-range of immune-mediated diseases, included IBD. We found that IRF5 is the single most important genetic determinant of the inter- individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, how IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA IC&IIC). Key to IBD pathogenesis is the ability of myeloid cells to clear microbes; however, how IRF5 regulates clearance of both resident and pathogenic intestinal microbes is not known (SA III). Multiple cell subsets can contribute to intestinal immune dysregulation, and limited in vivo studies in IRF5-/- mice have also demonstrated a role for IRF5 in T cell outcomes, with decreased Th1 differentiation in lupus model systems. However, whether IRF5 regulates T cell outcomes in a T cell-intrinsic (SA I) or T cell-extrinsic (SA II) manner is not known, including in intestinal tissues. We hypothesize that IRF5 will contribute to multiple immune cell functions essential in intestinal immune homeostasis in vivo through its role in both myeloid and T cell subsets, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens. We further hypothesize that IRF5 IBD-associated polymorphisms will modulate the identified roles for IRF5 in these pertinent immune outcomes. We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis