Mechanisms Regulating Innate Immune Responses

调节先天免疫反应的机制

基本信息

批准号：
9194584
负责人：
CLARA ABRAHAM
金额：
$ 34.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9194584
关键词：
Bacteria Biological Models Cell Differentiation process Cell physiology Cells Colitis Communicable Diseases Cytokine Signaling Data Disease Equilibrium Figs - dietary Genetic Determinism Genetic Polymorphism Genotype Goals Homeostasis Host Defense Human Immune Immune response In Vitro Individual Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestines Lead Lupus Mediating Microbe Modeling Mus Myelogenous Myeloid Cell Activation Myeloid Cells Outcome Pathogenesis Pattern recognition receptor Peripheral Population Predisposition Role Stimulus Structure of thyroid parafollicular cell Surface System T-Cell Activation T-Cell Activation Pathway T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Variant abstracting commensal microbes cytokine disorder risk gut microbiota immune function improved in vivo inter-individual variation macrophage microbial microorganism interaction pathogen pathogenic bacteria response risk variant

项目摘要

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

项目概要/摘要宿主与微生物之间的相互作用对于粘膜表面至关重要。失调这些相互作用可能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激活以及微生物清除。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 的介导机制发病机制，从而最终改善人类 IBD 的管理和治疗。 IRF5 区域的多态性与多种免疫介导的疾病相关，包括炎症性肠病。我们发现IRF5是间质性的最重要的遗传决定因素。 PRR 引发的信号传导和来自骨髓来源细胞的细胞因子的个体差异人口; IRF5疾病风险多态性的携带者在体内分泌高水平的细胞因子对一系列 PRR 刺激的反应。尽管 IRF5 在调节个体间的重要性人骨髓源性 PRR 诱导细胞因子的变化，IRF5 如何促进 IBD 尚未检查体内发病机制（SA IC&IIC）。 IBD 发病机制的关键是骨髓细胞清除微生物；然而，IRF5 如何监管居民和致病性肠道微生物尚不清楚（SA III）。多种细胞亚群有助于肠道免疫失调以及 IRF5-/- 小鼠的有限体内研究也证明了 IRF5 在 T 细胞结果中的作用，以及狼疮模型系统中 Th1 分化的降低。然而， IRF5 是否以 T 细胞内在 (SA I) 或 T 细胞外在 (SA II) 方式调节 T 细胞结果未知，包括肠道组织。我们假设 IRF5 将有助于多种免疫细胞通过其在体内的作用在肠道免疫稳态中发挥重要作用骨髓细胞和 T 细胞亚群，虽然它可能会导致结肠炎的炎症结果，但它对于调节肠道病原体至关重要。我们进一步假设 IRF5 IBD 相关多态性将调节 IRF5 在这些相关免疫结果中的作用。我们将把原代人类细胞研究与小鼠体内研究相结合，以剖析 IRF5 的贡献 IBD发病机制