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

总结 MHC类基因座与几种疾病有关。值得注意的是，全基因组人群研究 已经确定了MHC III类（MHC-III）基因内的关键多态性，这些基因与以下疾病直接相关： 自身免疫性疾病，包括1型糖尿病（T1 D）、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。虽然不太了解， MHC-III基因的表达模式与疾病的严重程度相关，既依赖于也不依赖于 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， 对疾病严重程度的敏感性。然而，关于基础机制仍有许多未知之处， MHC-III基因在指导自身免疫中的功能。这一重大差距阻碍了我们对集体的理解。 以及这些基因簇在健康和疾病中的相互作用。此外，这继续限制 基于免疫疗法的临床成功主要是由于我们对驱动免疫疗法的控制因素的不完全了解， 骨髓细胞生物学这是重要的，因为抗原呈递髓样细胞的功能失败，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。因此，我们认为， 这些研究的长期目标是确定MHC-III基因在 抗原呈递髓样细胞及其对炎性疾病的贡献。为了帮助解决现有的 鉴于该领域内的知识差距，拟议的一系列调查将确定MHC-III的职能作用 驱动促炎反应的基因（Aim 1）和它们在引发自身反应性T细胞反应中的作用（Aim 2）。广泛的初步调查进行了公正的高通量转录组学分析 结合RNAi筛选，以确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DC。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 使用一种新型的3D类器官。这些研究还将进一步确定关键的MHC-III基因在启动免疫应答中的机制。 以及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基因在体内控制T细胞引发中的关键作用。研究 将监测自身抗原特异性T细胞的频率、浸润和效应反应的变化， DC亚群中关键MHC-III基因的表达，以严格定义其免疫调节作用。总的来说， 了解MHC-III基因在自身免疫性疾病下调节巨噬细胞和DC生物学的决定因素 这些条件将对有效设计新的免疫疗法具有广泛的意义。

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.