Role of Complement-Driven Pulmonary Vascular Inflammation in PH

项目摘要/摘要 炎症是PH发病机制的核心，是人类和实验性疾病的明显触发因素，包括 自身免疫性硬皮病和血吸虫病感染。阻断炎症预防临床前的肺高压 模型，包括血吸虫病和缺氧性无菌炎症。然而，针对炎症面部 重大挑战，因为目前还没有任何治疗方法被证明具有临床益处。潜在机制 限制这种治疗方法的因素包括：非靶向免疫抑制抑制两者都有害 和保护路径；患者对患者的异质性导致只有一些患者子集受益， 在没有生物标志物识别的情况下；以及炎症对血管病理的不同贡献 病程。我们的研究小组，在这份PPG提交的背景下工作，独特地准备好 询问PH患者先天免疫和获得性免疫之间的联系机制。我们关注的是 补体、单核细胞和巨噬细胞参与天然免疫，CD4T细胞参与获得性免疫。我们的 研究表明，由血吸虫感染驱动的II型获得性免疫(导致 血吸虫病是多环芳烃的主要病因)，通过募集Ly6c来触发先天免疫反应 单核细胞，导致血管周围血栓反应蛋白-1(TSP-1)表达，导致潜在的转化生长因子-β激活 这导致了血管病变。我们现在建议利用明确定义的抗原触发器和 血吸虫-PH中询问补体如何激活适应性的机械性中间和终点 和先天免疫导致血管重塑。我们将研究疾病的潜在机制 持续性与恢复性，关注补体和激活的转化生长因子-β的潜在双重作用 激发PH，继而抑制血吸虫引发的炎症和PH作为抗原 负担被清除了。我们的第三个目标是翻译，研究外周血免疫细胞的表型 与血吸虫病、特发性和硬皮病相关的补体和TSP-1的关系 肺动脉高压，支持我们研究的总体严谨性和影响。假设：作为一种 先天触发获得性免疫，补体激活是2型炎症所必需的，单核细胞 TSP-1募集和激活转化生长因子-β，最初促进PH，后来帮助解决 血吸虫引起的炎症和PH。具体目标1：确定补体对于 2型炎症驱动的PH。特异性目标2：测定补体依赖TSP-1单核细胞 招募有助于血吸虫触发的最初发展和随后的解决 炎症和PH。具体目标3：确定外周血补体水平与 血吸虫病、硬皮病和特发性帕金森病患者的白细胞和细胞因子特征。我们的 总体目标是确定新的治疗目标，以安全和有效地针对潜在疾病驱动因素 PH值，有意义地影响疾病的进程。

Project Summary/Abstract Inflammation is central to PH pathogenesis, as a clear trigger of human and experimental disease including autoimmune scleroderma and schistosomiasis infection. Blocking inflammation prevents PH in pre-clinical models, including schistosomiasis and hypoxic sterile inflammation. However, targeting inflammation faces significant challenges, as no therapies have yet been proven to be of clinical benefit. Potential mechanisms that limit this therapeutic approach include: non-targeted immunosuppression suppressing both deleterious and protective pathways; patient-to-patient heterogeneity resulting in only some subsets of patients benefiting, without biomarker identification; and a variable contribution of inflammation to vascular pathology over the disease course. Our research group, working within the context of this PPG submission, is uniquely poised to interrogate mechanisms that link innate and adaptive immunity in PH. We focus on the interplay between complement, monocytes and macrophages in innate immunity, and CD4 T cells in adaptive immunity. Our body of work has demonstrated that Type 2 adaptive immunity driven by Schistosoma exposure (the cause of schistosomiasis, a major PAH etiology), triggers an innate immune response with recruitment of Ly6c+ monocytes, resulting in perivascular thrombospondin-1 (TSP-1) expression, leading to latent TGF-β activation that drives the vascular pathology. We now propose to leverage clearly defined antigenic triggers and mechanistic intermediate and endpoints in Schistosoma-PH to interrogate how complement activates adaptive and innate immunity resulting in vascular remodeling. We will study mechanisms underlying disease persistence versus recovery, focusing on potential dual roles of complement and activated TGF-β as initially inciting of PH, and subsequently suppressing Schistosoma-triggered inflammation and PH as the antigenic burden is cleared. Our third Aim is translational, investigating the peripheral blood immune cell phenotype as it relates to complement and TSP-1 in subjects schistosomiasis, idiopathic and scleroderma-associated pulmonary arterial hypertension, supporting the overall rigor and impact of our studies. Hypothesis: As an innate trigger of adaptive immunity, complement activation is necessary for Type 2 inflammation, monocyte recruitment, and activation of TGF-β by TSP-1, initially contributing to PH and later helping in the resolution of Schistosoma-induced inflammation and PH. Specific Aim 1: To determine that complement is necessary for Type 2 inflammation-driven PH. Specific Aim 2: To determine that complement-dependent TSP-1+ monocyte recruitment contributes to both the initial development and subsequent resolution of Schistosoma-triggered inflammation and PH. Specific Aim 3: To determine that peripheral blood complement levels correlate with leukocyte and cytokine signatures in humans with schistosomiasis, scleroderma and idiopathic PAH. Our overall goal is to identify novel therapeutic targets to safely and effectively target underlying disease drivers in PH, to meaningfully impact the disease course.