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: 10429530
• 负责人: Michael W Lipscomb
• 金额: $ 19.38万
• 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/10429530
• 关键词: 3-Dimensional; Antigen Presentation; Antigens; 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; Lead; MHC Class I Genes; 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; Rheumatoid Arthritis; Role; Series; Severity of illness; Signal Transduction; Spontaneous colitis; System; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Tissues; Tumor-infiltrating immune cells; Variant; Work; adaptive immune response; antigen-specific T cells; autoreactive T cell; autoreactivity; base; combat; design; effective therapy; follow-up; gene function; genome-wide; immunoregulation; in vivo; innovation; insight; insulitis; macrophage; mouse model; novel; novel therapeutics; prevent; public health relevance; repaired; response; screening; success; systemic autoimmune disease; transcriptomics

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.

摘要 MHC类基因与几种疾病有关。值得注意的是，全基因组人口研究 已确定MHC III类(MHC-III)基因中的关键多态与 自身免疫性疾病，包括1型糖尿病(T1D)、肠道疾病(IBD)、系统性狼疮 红斑狼疮(SLE)和类风湿性关节炎(RA)等。尽管知之甚少，但 MHC-III基因的表达模式与疾病严重程度相关，既依赖于也不依赖于 MHC I类和II类区域内与易感性相关的多态。这表明MHC-III 在自身免疫环境中，基因可以控制免疫力与耐受性，基因变异可能会增加 对疾病严重程度的易感性。然而，托换机理仍有许多未知之处。 MHC-III基因在指导自身免疫中的作用。这一重大差距阻碍了我们对集体的理解 以及这些聚集的基因在健康和疾病中的相互联系的作用。此外，这继续限制了 免疫疗法的临床成功在很大程度上是由于我们对驱动因素的不完全了解 髓系细胞生物学。这一点很重要，因为抗原提呈髓系细胞的功能失败，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。因此， 这些研究的长期目标是确定MHC-III基因在糖尿病中的潜在机制作用。 抗原提呈髓系细胞及其在炎症性疾病中的作用。帮助解决现有的 鉴于该领域内的知识差距，拟议的一套调查将确定MHC-III的功能作用 促炎症反应基因(AIM 1)及其在启动自身反应性T细胞反应(AIM)中的作用 2)。广泛的初步调查进行了无偏见的高通量转录图谱 结合RNAi筛选以确定被认为在巨噬细胞中发挥关键功能的关键MHC-III基因 和华盛顿。在目标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。 使用了一种新的3D有机体。这些研究还将确定关键的MHC-III基因在启动过程中的机制 以及使用胰岛素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基因在体内控制T细胞启动的关键作用。研究 将监测自身抗原特异性T细胞缺失时的频率、渗透和效应反应的变化 对DC亚群中的关键MHC-III基因进行分类，以严格定义其免疫调节作用。总而言之， 了解自身免疫状态下MHC-III基因调控巨噬细胞和DC生物学的决定因素 这些条件将对新型免疫疗法的有效设计产生广泛影响。