Role of Complement-Driven Pulmonary Vascular Inflammation in PH

项目概要/摘要 炎症是 PH 发病机制的核心，是人类和实验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。阻断炎症可预防临床前PH 模型，包括血吸虫病和缺氧无菌性炎症。然而，针对炎症面临着 重大挑战，因为尚未证明任何疗法具有临床益处。潜在机制 限制这种治疗方法的因素包括： 非靶向免疫抑制 和保护途径；患者之间的异质性导致只有部分患者受益， 没有生物标志物鉴定；以及炎症对血管病理学的不同贡献 病程。我们的研究小组在本 PPG 提交的背景下工作，具有独特的优势 探究 PH 中先天免疫和适应性免疫之间的联系机制。我们关注之间的相互作用 先天免疫中的补体、单核细胞和巨噬细胞，以及适应性免疫中的 CD4 T 细胞。我们的 大量工作已经证明，2 型适应性免疫是由血吸虫暴露（血吸虫感染的原因）驱动的。 血吸虫病（PAH 的主要病因），通过募集 Ly6c 来触发先天免疫反应 单核细胞，导致血管周围血小板反应蛋白-1 (TSP-1) 表达，导致潜在的 TGF-β 激活 驱动血管病理学。我们现在建议利用明确定义的抗原触发因素和 Schistosoma-PH 的机械中间体和终点，以探究补体如何激活适应性 和先天免疫导致血管重塑。我们将研究疾病的机制 持久性与恢复，重点关注补体和激活的 TGF-β 的潜在双重作用 刺激 PH，随后抑制血吸虫引发的炎症和作为抗原的 PH 负担被清除。我们的第三个目标是转化，研究外周血免疫细胞表型，因为它 与血吸虫病、特发性和硬皮病相关受试者中的补体和 TSP-1 相关 肺动脉高压，支持我们研究的整体严谨性和影响力。假设：作为 适应性免疫的先天触发因素，补体激活对于 2 型炎症、单核细胞是必需的 TSP-1 募集和激活 TGF-β，最初有助于 PH，后来有助于解决 血吸虫引起的炎症和PH。具体目标 1：确定补足是必要的 2 型炎症驱动的 PH。具体目标 2：确定补体依赖性 TSP-1 单核细胞 招募有助于血吸虫引发的最初发展和随后的解决 炎症和PH值。具体目标 3：确定外周血补体水平与 血吸虫病、硬皮病和特发性肺动脉高压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靶点，以安全有效地针对潜在的疾病驱动因素 PH，对病程产生有意义的影响。

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.