Delineating the function of MHC class III genes in antigen presenting myeloid cell contribution to autoimmunity

描述 MHC III 类基因在抗原呈递骨髓细胞对自身免疫的贡献中的功能

• 批准号: 10641866
• 负责人: Michael W Lipscomb
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641866
• 关键词: 3-Dimensional; Antigen Presentation; Antigen-Presenting Cells; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Biocompatible Materials; Biological Assay; CRISPR screen; Cellular biology; Clinical; Colitis; Coupled; Data; Dendritic Cells; Development; Disease; Disease Progression; Disease susceptibility; Environment; Equilibrium; Evaluation; Failure; Foundations; Frequencies; Gene Cluster; Genes; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Health; Immune; Immune response; Immunity; Immunobiology; Immunotherapy; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Knowledge; MHC Class I Genes; Macrophage; Measures; Modeling; Monitor; Myeloid Cells; Onset of illness; Organ; Organoids; Pathology; Pattern; Pharmacotherapy; Physiological; Pilot Projects; Play; Population Study; Predisposition; Publishing; RNA Interference; RNA interference screen; Repression; Rheumatoid Arthritis; Role; Series; Severity of illness; Signal Transduction; Spontaneous colitis; System; Systemic Lupus Erythematosus; T cell infiltration; T cell response; T-Lymphocyte; Tissues; Variant; Work; adaptive immune response; antigen-specific T cells; autoreactive T cell; autoreactivity; combat; design; effective therapy; follow-up; gene function; genome-wide; genomic locus; immunoregulation; in vivo; innovation; insight; insulitis; mouse model; novel; novel therapeutics; prevent; public health relevance; repaired; response; screening; success; systemic autoimmune disease; transcriptomic profiling

SUMMARY The MHC class locus has been associated with several diseases. Notably, genome-wide population studies have identified pivotal polymorphisms within MHC class III (MHC-III) genes that are directly associated with autoimmune diseases, including type 1 diabetes (T1D), intestinal bowel disease (IBD), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), among others. Although less understood, variations in expression patterns of MHC-III genes correlate with disease severity, both dependent and independent from predisposition-related polymorphisms within the MHC class I and II regions. This would suggest that MHC-III genes can govern immunity vs. tolerance in autoimmune settings, with genetic variations potentially increasing susceptibility to disease severity. However, much remains unknown regarding the underpinning mechanistic functions of MHC-III genes in directing autoimmunity. This major gap prevents our understanding of the collective and interconnective roles of these clustered genes in health and disease. Furthermore, this continues to limit clinical success in immune-based therapies largely due to our incomplete knowledge of governing factors driving myeloid cell biology. This is important as failures in the function of antigen presenting myeloid cells, such as dendritic cells (DC) and macrophages, can cause organ-specific and systemic autoimmune diseases. Therefore, it is the long-term objective of these studies to determine the underlying mechanistic role of MHC-III genes in antigen presenting myeloid cells and their contribution to inflammatory diseases. To help resolve the existing knowledge gap within the field, the proposed set of investigations will determine the functional role of MHC-III genes in driving pro-inflammatory responses (Aim 1) and their role in priming autoreactive T cell responses (Aim 2). Extensive preliminary investigations have performed an unbiased high-throughput transcriptomic profiling coupled with RNAi screening to identify key MHC-III genes believed to play key functional roles in macrophages and DC. In Aim 1, studies will intricately evaluate the role of candidate MHC-III genes in macrophages in vitro using a novel 3D organoid. The studies will additionally define the mechanisms of key MHC-III genes in initiating and sustaining inflammation in vivo using both insulitis and colitis autoimmune mouse models. For Aim 2, investigations will describe the pivotal role of MHC-III genes in governing the priming of T cells in vivo. Studies will monitor changes in frequency, infiltration and effector responses of autoantigen-specific T cells in absence of key MHC-III genes within DC subsets to rigorously define their immunoregulatory roles. Collectively, understanding the determinants of MHC-III genes in regulating macrophage and DC biology under autoimmune conditions would have broad implications for effective design of novel immunotherapies.

概括 MHC类基因座与多种疾病有关。值得注意的是，全基因组人口研究 已经确定了与直接相关的MHC III（MHC-III）基因中的关键多态性 自身免疫性疾病，包括1型糖尿病（T1D），肠肠疾病（IBD），全身性狼疮 红斑（SLE）和类风湿关节炎（RA）等。尽管不了解，但变化 MHC-III基因的表达模式与疾病严重程度相关，无论是依赖而独立于 MHC I类和II区域内与易感性相关的多态性。这表明MHC-III 基因可以控制自身免疫环境中的免疫力与公差，遗传变异可能增加 对疾病严重程度的敏感性。但是，关于基础机制仍然未知 MHC-III基因在指导自身免疫性中的功能。这个主要差距阻止了我们对集体的理解 这些聚类基因在健康和疾病中的互连作用。此外，这继续限制 基于免疫疗法的临床成功很大程度上是由于我们对驾驶因素的不完整了解 髓样细胞生物学。这很重要，因为抗原呈现髓样细胞的功能的失败，例如 树突状细胞（DC）和巨噬细胞可引起器官特异性和全身性自身免疫性疾病。所以， 这些研究的长期目标是确定MHC-III基因在 抗原呈现髓样细胞及其对炎症性疾病的贡献。帮助解决现有 在该领域内的知识差距，拟议的一组研究将确定MHC-III的功能作用 驱动促炎反应的基因（AIM 1）及其在启动自动反应性T细胞反应中的作用（AIM 2）。广泛的初步研究已经进行了公正的高通量转录组分析 结合RNAi筛选，以识别据信在巨噬细胞中起关键功能作用的关键MHC-III基因 和DC。在AIM 1中，研究将复杂地评估候选MHC-III基因在体外巨噬细胞中的作用 使用新颖的3D器官。这些研究还将定义关键MHC-III基因启动时的机制 并使用胰岛炎和结肠炎自身免疫小鼠模型在体内维持炎症。对于目标2， 研究将描述MHC-III基因在治理体内启动中的关键作用。研究 将监测自身抗原特异性T细胞的频率，浸润和效应子响应的变化 DC子集中的关键MHC-III基因的严格定义其免疫调节作用。共同 了解在自身免疫性下调节巨噬细胞和DC生物学中MHC-III基因的决定因素 条件将对新型免疫疗法的有效设计具有广泛的影响。