Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension

总结/摘要 炎症在肺动脉高压（PAH）的发病机制中起重要作用，但是否 炎症是因果关系，替代触发机制的放大器，还是附带现象仍不清楚。 在此领域的先前研究主要集中在先天免疫、不育模型和单个细胞因子或细胞 在缺乏明确的病理生物学背景的情况下， 免疫或先天适应性免疫串扰。解决这些 局限性，我们的小组研究寄生虫血吸虫，血吸虫病的原因，这可能是最 PAH是世界范围内的一种流行形式。使用血吸虫-肺动脉高压（PH）小鼠模型， 前期鉴定了一系列对PH发展至关重要的机制事件： 肺中的CD 4 T细胞;将CCR 2 + Ly 6c+单核细胞募集到外膜间隙，表达 血小板反应蛋白-1（TSP-1）;并且TSP-1功能性地激活潜伏的TGF-β，引起血管重塑。 这个建议建立在这个基础上，现在询问适应性和先天免疫接口，我们 认为是血吸虫PH致病所必需的。我们将我们的研究扩展到翻译分析 人类生物标本，寻找与重度PAH高危人群中PAH存在相关的蛋白质 血吸虫病这项提议将检验肺内树突状细胞（DC）存在的假设， 血吸虫抗原对支持Th 2极化的CD 4 T细胞，引起间质性 巨噬细胞（IM），其释放CCR 2配体CCL 2、7和12，驱动TSP-1+单核细胞募集， 我们还假设增加PAH风险的关键蛋白质，包括CCL 2， CCL 7、CCL 12和TSP-1-可在人血浆中检出。我们提出四个目标。目标1将确定， 血吸虫PH中T细胞活化需要特异性DC亚群cDC 2s的抗原呈递。目的2 将确定Th 1与Th 2炎症的平衡是否驱动单核细胞/巨噬细胞和PH表型， 血吸虫-PH. Aim 3将确定TSP 1+单核细胞需要IM释放CCL 2/7/12 目的4将鉴定与受试者PAH发展相关的血浆蛋白 血吸虫病这一转化目标将通过开发和表征两个队列来实现， 从巴西4个临床中心招募的受试者：血吸虫病前驱疾病受试者 根据超声心动图筛查不太可能患有PAH的肝脾疾病（SchHSD）， 和患有右心导管插入术证实的PAH的SchHSD受试者。完成这些研究将 导致理解先天性和适应性免疫在血吸虫-PAH发展中的作用， 为诊断和潜在治疗这种疾病的全新方法创造了机会。我们提出 确定与血液中疾病存在相关的机制蛋白，促进风险筛查 低资源地区的问题。

Summary/Abstract Inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH), but whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies in this area have largely focused on innate immunity, sterile models, and single cytokines or cells in the absence of a well-defined pathobiological context—approaches that cannot address aspects of adaptive immunity or innate-adaptive immunity crosstalk which contribute to vascular disease. To address these limitations, our group studies the parasite Schistosoma, the cause of schistosomiasis which may be the most prevalent form of PAH worldwide. Using a Schistosoma-pulmonary hypertension (PH) murine model, studies in the prior period identified a series of mechanistic events which are critical for PH development: Th2-activation of CD4 T cells in the lungs; which recruit of CCR2+ Ly6c+ monocytes to the adventitial space that express thrombospondin-1 (TSP-1); and the TSP-1 functionally activates latent TGF-β, causing vascular remodeling. This proposal builds on this foundation by now interrogating adaptive and innate immune interfaces that we believe to be necessary to Schistosoma-PH pathogenesis. We extend our studies to translational analysis of human biospecimens, seeking proteins that correlate with PAH presence in an at-risk group with severe schistosomiasis. This proposal will test the hypothesis that intrapulmonary dendritic cells (DCs) present Schistosoma antigen to CD4 T cells which support Th2 polarization, causing activation of interstitial macrophages (IMs), who release the CCR2 ligands CCLs 2, 7 and 12, driving TSP-1+ monocyte recruitment, TGF-β activation, and PH. We also hypothesize that key proteins that increase risk of PAH—including CCL2, CCL7, CCL12, and TSP-1—can be detected in human plasma. We propose 4 Aims. Aim 1 will determine that antigen presentation by a specific DC subset, cDC2s, is required for T cell activation in Schistosoma-PH. Aim 2 will determine if the balance of Th1 to Th2 inflammation drives monocyte/macrophage and PH phenotypes in Schistosoma-PH. Aim 3 will determine that CCL2/7/12 release by IMs is required for TSP1+ monocyte recruitment in Schistosoma-PH. Aim 4 will identify plasma proteins associated with PAH development in subjects with schistosomiasis. This translational Aim will be achieved by developing and characterizing two cohorts of subjects recruited from 4 clinical centers in Brazil: subjects with the precursor condition schistosomiasis hepatosplenic disease (SchHSD) who are unlikely to have PAH on the basis of echocardiography screening, and subjects with SchHSD who have right heart catheterization-confirmed PAH. Completion of these studies will lead to understanding the role of innate and adaptive immunity in the development of Schistosoma-PAH, and create opportunities for entirely novel approaches to diagnosing and potentially treating this disease. We propose to identify mechanistic proteins which correlate with disease presence in blood, facilitating screening of at-risk subjects in low-resource areas.