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

基本信息

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
项目类别：
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

项目摘要

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相关。值得注意的是，全基因组人群研究已鉴定出与 MHC III 类 (MHC-III) 基因直接相关的关键多态性自身免疫性疾病，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。尽管了解较少，但存在差异 MHC-III 基因的表达模式与疾病严重程度相关，既依赖又独立 MHC I 类和 II 类区域内的易感性相关多态性。这表明 MHC-III 基因可以控制自身免疫环境中的免疫与耐受性，遗传变异可能会增加对疾病严重程度的易感性。然而，关于其基础机制仍然有很多未知之处。 MHC-III 基因在指导自身免疫方面的功能。这一重大差距阻碍了我们对集体的理解以及这些聚集基因在健康和疾病中的相互关联的作用。此外，这继续限制免疫疗法的临床成功很大程度上是由于我们对驱动因素的不完全了解骨髓细胞生物学。这很重要，因为抗原呈递骨髓细胞的功能失败，例如树突状细胞（DC）和巨噬细胞可引起器官特异性和系统性自身免疫性疾病。所以，这些研究的长期目标是确定 MHC-III 基因在抗原呈递骨髓细胞及其对炎症性疾病的贡献。为帮助解决现有由于该领域内的知识差距，拟议的一系列调查将确定 MHC-III 的功能作用驱动促炎症反应的基因（目标 1）及其在引发自身反应性 T 细胞反应中的作用（目标 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 筛选来鉴定被认为在巨噬细胞中发挥关键功能作用的关键 MHC-III 基因和直流电。在目标 1 中，研究将在体外复杂地评估候选 MHC-III 基因在巨噬细胞中的作用使用新颖的 3D 类器官。这些研究还将进一步明确关键 MHC-III 基因在启动过程中的机制。并使用胰岛炎和结肠炎自身免疫小鼠模型维持体内炎症。对于目标 2，研究将描述 MHC-III 基因在控制体内 T 细胞启动中的关键作用。研究将监测自身抗原特异性 T 细胞在缺失情况下的频率、浸润和效应反应的变化 DC 子集中的关键 MHC-III 基因，以严格定义其免疫调节作用。总的来说，了解自身免疫下 MHC-III 基因在调节巨噬细胞和 DC 生物学中的决定因素条件将对新型免疫疗法的有效设计产生广泛的影响。