Mechanisms Regulating Innate Immune Responses

调节先天免疫反应的机制

基本信息

批准号：
9304966
负责人：
CLARA ABRAHAM
金额：
$ 41.88万
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/9304966
关键词：
Bacteria Biological Models Cell Differentiation process Cell physiology Cells Colitis Communicable Diseases Data Disease Equilibrium Genetic Determinism Genetic Polymorphism Genotype Goals Homeostasis Host Defense Human Immune In Vitro Individual Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Innate Immune Response Intestines Lead Lupus Mediating Microbe Modeling Mus Myelogenous Myeloid Cell Activation Myeloid Cells Outcome Pathogenesis Pathogenicity Pathway interactions Pattern recognition receptor Peripheral Population Predisposition Role Signal Transduction Stimulus Surface System T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Variant commensal microbes cytokine disorder risk gut microbiota host-microbe interactions immune function improved in vivo inter-individual variation macrophage microbial 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

项目摘要/摘要宿主：微生物相互作用之间的相互作用在粘膜表面至关重要。失调这些相互作用会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反应导致细胞因子和细胞活化的分泌，以及微生物清除。这些结果之间的平衡会影响炎症之间的敏感性疾病和传染病。我们的长期目标是了解介导IBD的机制发病机理，最终改善了人类IBD的管理和治疗。 IRF5区域的多态性与广泛的免疫介导的疾病有关，包括IBD。我们发现IRF5是间间最重要的遗传决定因素来自PRR引起的信号传导和细胞因子的个体变化来自整个髓样细胞人口; IRF5疾病风险多态性的载体分泌高水平的细胞因子对一系列PRR刺激的响应。尽管IRF5在调节个体之间很重要人髓样衍生的PRR诱导的细胞因子的变化，IRF5如何贡献IBD 尚未检查体内发病机理（SA IC＆IIC）。 IBD发病机理的关键是髓样细胞清除微生物；但是，IRF5如何调节居民和致病性肠道微生物尚不清楚（SA III）。多个细胞子集可能有助于肠道免疫失调和在IRF5 - / - 小鼠中的体内研究有限，也证明了对 T细胞结局中的IRF5，狼疮模型系统中Th1分化的降低。然而， IRF5是否调节T细胞中的T细胞结局（SA I）或T细胞效法（SA II）的方式是未知，包括在肠组织中。我们假设IRF5将有助于多个免疫细胞在体内的作用在体内至关重要的。髓样和T细胞子集，尽管它可能导致结肠炎的炎症结果，但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在这些相关的免疫结果中的鉴定作用。我们将将对原代人细胞的研究与体内小鼠研究进行剖析，以剖析IRF5的贡献到IBD发病机理