HLA-G effector mechanisms in asthma

哮喘中的 HLA-G 效应机制

• 批准号: 8196611
• 负责人: Anne I. Sperling
• 金额: $ 32.14万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196611
• 关键词: Adult; Affect; Asthma; Binding; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Code; Complement; Data; Epigenetic Process; Exhibits; Family member; Functional disorder; Genes; Genetic Variation; Genotype; Goals; HLA G antigen; Human; Immune; Immune response; Immune system; Lung; Muscle function; Mutation; Organ; Pathogenesis; Pathway interactions; Phenotype; Production; Proteins; Receptor Gene; Regulation; Risk; Severities; Signal Transduction; Study Subject; T-Lymphocyte; Testing; Variant; airway inflammation; base; bronchial epithelium; cytokine; immune activation; immune function; immunoregulation; insight; memory CD4 T lymphocyte; novel therapeutics; receptor; receptor expression; respiratory smooth muscle; response; volunteer

Genetic variation in HLA-G that regulates HLA-G protein production influences asthma risk, and coding variations in HLA-G receptor genes {LILRBI and LILRB2 and their family member LILRB4) also confer risk for bronchial hyperresponsiveness and/or asthma. While these findings imply that HLA-G - LILRB signaling participates in asthma pathogenesis, they do not reveal the operative mechanisms. HLA-G can modulate immune function, and independently alters airway smooth muscle (ASM) phenotype, raising the possibility that genetic alteration of HLA-G abundance or of LILRB signaling confers asthma risk by affecting the immune system, by modulating effector organ (ASM) function, or both. The major objective of this project is to discern how HLA-G - LILRB signaling participates in asthma pathogenesis. We recently found that HLA-G is secreted from bronchial epithelium, that its abundance in BAL fluid is increased in asthma, and that BAL HLA-G concentration increases with asthma severity (see Project 1). Others have demonstrated that the immune phenotype of lung CD4 T cells reflects predominantly Th17 skewing in severe asthmatics, while more Th2 skewing is found in less severe asthmatics. We hypothesize that prevailing HLA-G abundance modulates immune activation state or alters immunological responses, with higher levels of HLA-G promoting the severe asthmatic immune phenotypes. We have recently associated genetic variations in LILRBI, LILRB2, and LILRB4 with asthma risk. Since HLA-G exerts its effects through LILRB receptors, any functional consequences of LILRB gene variations could modulate the influence of HLA-G on the immune system. Our preliminary data also demonstrate that HLA-G - LILRB signaling modulates ASM function. It is thus also conceivable that functional variation in LILRB receptors modulates asthma severity by influencing the ability of HLA-G to induce asthma-like ASM dysfunction. The goals of Project 2 are therefore to: 1) determine whether and how HLA-G affects immune responses; 2) determine the effect of LILBR genotype on immune modulation by HLA-G; and 3) determine the effect of LILBR genotype on HLA-G signaling to airway smooth muscle. We will exploit naturally occurring genetic variation in HLA-G receptors to dissect these possible mechanisms of action. This project relies heavily on biospecimens obtained from human asthmatic volunteers through Core B, and synergistically complements Projects 1 and 3, in which the regulation of HLA-G expression and epigenetic correlates of asthma are determined in the same subjects studied here.

调节HLA-G蛋白产生的HLA-G遗传变异影响哮喘风险， HLA-G受体基因（LILRB 1和LILRB 2及其家族成员LILRB 4）的变异也会导致风险 治疗支气管高反应性和/或哮喘虽然这些发现意味着HLA-G - LILRB信号转导 参与哮喘的发病机制，但尚未揭示其作用机制。HLA-G可以调节 免疫功能，并独立改变气道平滑肌（ASM）表型，提高了可能性， HLA-G丰度或LILRB信号的遗传改变通过影响免疫系统而赋予哮喘风险， 系统，通过调节效应器官（ASM）功能，或两者兼而有之。这个项目的主要目标是辨别如何 HLA-G - LILRB信号通路参与哮喘发病机制。我们最近发现，HLA-G是由 支气管上皮细胞，其在支气管液中的丰度在哮喘中增加， 随着哮喘的严重程度增加（见项目1）。其他人已经证明，肺的免疫表型 在重度哮喘患者中，CD 4 T细胞主要反映Th 17的偏移，而更多的Th 2偏移被发现 在不太严重的哮喘患者中。我们假设HLA-G的丰度调节免疫激活 状态或改变免疫反应，高水平的HLA-G促进严重哮喘免疫 表型我们最近将LILRB 1、LILRB 2和LILRB 4的遗传变异与哮喘风险相关联。 由于HLA-G通过LILRB受体发挥其作用，LILRB基因变异的任何功能性后果 可以调节HLA-G对免疫系统的影响。我们的初步数据还表明， HLA-G - LILRB信号转导调节ASM功能。因此，也可以想象LILRB中的功能变化 受体通过影响HLA-G诱导哮喘样ASM功能障碍的能力来调节哮喘的严重程度。 因此，项目2的目标是：1）确定HLA-G是否以及如何影响免疫应答; 2） 确定LILBR基因型对HLA-G免疫调节的影响;和3）确定LILBR基因型对HLA-G免疫调节的影响 基因型对HLA-G信号传导至气道平滑肌的影响。我们将利用自然发生的遗传变异， HLA-G受体来剖析这些可能的作用机制。这个项目在很大程度上依赖于生物标本 通过核心B从人类哮喘志愿者获得，并协同补充项目1和3， 其中HLA-G表达的调节和哮喘的表观遗传学相关性在相同的细胞中确定， 这里研究的课题。