HLA-G effector mechanisms in asthma

调节人类白细胞抗原-G蛋白产生的人类白细胞抗原-G基因变异影响哮喘风险和编码 人类白细胞抗原G受体基因的变异(LILRBI和LILRB2及其家族成员LILRB4)也增加了风险 治疗支气管高反应性和/或哮喘。虽然这些发现意味着人类白细胞抗原-G-LILRB信号 参与哮喘发病机制的研究，并未揭示其运行机制。人类白细胞抗原-G可以调节 免疫功能，并独立改变呼吸道平滑肌(ASM)表型，增加了 人类白细胞抗原G丰度或LILRB信号的基因改变通过影响免疫而增加哮喘的风险 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信号参与了哮喘的发病机制。我们最近发现，人类白细胞抗原-G是由 哮喘患者BAL液中BAL-G含量增加，BAL-G浓度升高。 随哮喘严重程度增加(见项目1)。其他人则证明了肺的免疫表型 在重症哮喘患者中，CD4T细胞主要反映Th17偏斜，而Th2偏斜更明显 在不太严重的哮喘患者中。我们假设盛行的人类白细胞抗原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促进重症哮喘免疫 表型。我们最近发现LILRBI、LILRB2和LILRB4基因变异与哮喘风险有关。 由于人类白细胞抗原-G通过LILRB受体发挥作用，因此LILRB基因变异的任何功能后果 可以调节人类白细胞抗原-G对免疫系统的影响。我们的初步数据也表明， HL A-G-LILRB信号调节ASM功能。因此，也可以想象LILRB中的函数变化 受体通过影响人类白细胞抗原G诱导哮喘样ASM功能障碍来调节哮喘的严重程度。 因此，项目2的目标是：1)确定人类白细胞抗原-G是否以及如何影响免疫反应；2) 检测LILBR基因对人类白细胞抗原G免疫调节的影响；3)检测LILBR基因对免疫调节的影响 基因分型对人类白细胞抗原-G信号传导的影响。我们将利用自然发生的遗传变异 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群落。 通过Core B从人类哮喘志愿者那里获得，并协同补充项目1和3， 其中，人类白细胞抗原-G表达的调节和哮喘的表观遗传相关性被同时确定 在这里学习的科目。

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.