Regulation and expression of HLA-G in asthmatic airways

在美国，哮喘影响着1700多万人，是发病的主要原因。最近有一个角色是 非经典的人类白细胞抗原-I类免疫因子--人类白细胞抗原-G。治疗哮喘的药物已被提出。直接或间接的人类白细胞抗原-G 刺激T抑制细胞的存在和功能，并下调T辅助细胞2的活性 (Th2)可能在哮喘发病机制中起关键作用的细胞。我们实验室的研究表明，人类白细胞抗原G和 哮喘易感基因，与哮喘相关的几个关键单核苷酸多态(SNPs) 表型：哮喘患者呼吸道中人类白细胞抗原-G的表达增加，而呼吸道上皮细胞 产生人类白细胞抗原G。我们AADCRC小组最近的观察表明，人类白细胞抗原-G在呼吸道中的表达 上皮细胞受Th2细胞产生的细胞因子调节，并且在呼吸道中发现了一个关键的人类白细胞抗原-G受体 平滑肌；激活该受体可刺激平滑肌的增殖和分化。因此，人类白细胞抗原-G 可能在改变呼吸道内的免疫和结构环境方面发挥关键作用。的总体目标 这个项目是为了证明在一项关于轻度和重度的纵向研究中存在局部、呼吸道的人类白细胞抗原-G。 并展示调节呼吸道上皮细胞局部产生人类白细胞抗原-G的机制。 我们认为，肺和外周局部表达的人类白细胞抗原-G可能与哮喘的表型有关。 我们进一步认为，人类白细胞抗原G基因同时影响循环和呼吸道中人类白细胞抗原G的丰度。 正如我们在项目2中指出的那样，人类白细胞抗原-G丰度的增加可能会导致平滑肌的重要变化 随着时间的推移会加重哮喘的表型。为了解决我们在此应用程序中的假设，我们提出了三个 具体目的：1)根据疾病严重程度和表型检测哮喘患者的HLA-G水平。我们假设 哮喘患者的循环和局部呼吸道中的HLA-G浓度都较高，这些浓度 部分依赖于SNP在其3‘-非翻译区(+3142)对人类白细胞抗原G的调节。2)确定 IL-13等Th2细胞因子对人类白细胞抗原-G表达的调节。我们假设IL-13会增加 人类白细胞抗原G在肺内主要来源的呼吸道上皮细胞中的表达和分泌，以及 随着时间的推移，这对持续的呼吸道炎症产生了积极的反馈。3)确定监管 用miRNA检测呼吸道上皮细胞中的HL A-G。我们假设+3142SNP可变地结合了能够 抑制人类白细胞抗原-G的表达，这些微小RNA是由呼吸道上皮细胞产生的。加在一起，这些 研究将清楚地了解人类白细胞抗原-G在哮喘中的作用以及Th2相关分子对其的调节 通过细胞因子和微RNA，从而为新疗法的开发奠定了基础。

Asthma affects over 17 million people in the United States and is a major cause of morbidity. Recently a role for a non-classical HLA class I immune factor, HLA-G. in asthma has been proposed. HLA-G directly or indirectly acts to stimulate the presence and function of T suppressor cells and to down-regulate the activity of T helper 2 (Th2) cells that may be critical to asthma pathogenesis. Studies from our laboratories suggest that is HLA-G an asthma susceptibility gene, that several key single nucleotide polymorphisms (SNPs) correlate with the asthma phenotype, that the presence of HLA-G is increased in the airways of asthmatics, and that airway epithelial cells produce HLA-G. More recent observations from our AADCRC group suggest that HLA-G expression in airway epithelium is regulated by cytokines produced by Th2 cells and that a key receptor for HLA-G is found in airway smooth muscle; activating this receptor stimulates smooth muscle proliferation and differentiation. Thus, HLA-G may have a key role in altering the Immune and structural environment within airways. The overall objectives of this project are to demonstrate the presence of local, airway HLA-G in a longitudinal study of mild and severe asthma and to demonstrate mechanisms that regulate the local production of HLA-G by airway epithelial cells. We propose that HLA-G expressed locally in the lung and in the periphery may contribute to the asthma phenotype. We further propose that HLA-G genotype influences both circulating and airway abundance of HLA-G The increased abundance of HLA-G may lead, as we note in Project 2, to important changes in smooth muscle phenotype that over time worsens asthma. To address our hypotheses in this application, we propose three specific aims: 1) Examine HLA-G levels in asthma based on disease severity and phenotype. We hypothesize that both circulating and local airway HLA-G concentrations are greater in patients with asthma, that these concentrations depend in part on the regulation of HLA-G by a SNP in its 3'-untranslated region (+3142). 2) Determine the regulation of HLA-G expression by Th2 cytokines such as IL-13. We hypothesize that IL-13 increases the expression and secretion of HLA-G in airway epithelium, the principal source of HLA-G in the lung, and that over time this creates a positive feedback for continued airway inflammation. 3) Determine regulation of HLA-G in airway epithelium by miRNA. We hypothesize that the +3142 SNP variably binds microRNA that can suppress HLA-G expression, and that these microRNA are produced by airway epithelial cells. Together, these studies will provide a clear understanding of the role of HLA-G in asthma and its regulation by Th2-associated cytokines and by microRNA, and thus set the stage for the development of novel new therapies.