Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression

有令人信服的证据表明炎症和自身免疫现象都参与了 PAH的发病机制。然而，引发和维持疾病的机制仍然难以捉摸。 基于其他疾病的新证据，包括关节炎、肾脏疾病和癌症，产生了 通过该项目的联合调查人员，已经清楚地表明，当补体系统受到失调时， 可能成为炎症驱动的组织损伤的有力煽动者。我们最近公布的数据 我们第一次证明，免疫球蛋白驱动的补体激活 肺血管周围区域的级联反应，特别是其替代途径，是一种重要的机制 实验性缺氧性PH(无菌的一种形式)启动促炎和促增殖过程 炎症“)。我们还证明了激活的补体级联和免疫球蛋白G(IgG)。 沉积是该病的持久决定因素。本提案以这些调查结果为基础，并 由机械臂和平移臂组成。在目标1中，我们将评估免疫球蛋白的作用 和补体在启动PH的促炎过程中的作用。在目标2中，我们将评估 免疫球蛋白和补体在血管损伤和疾病过程中的持续进展。在……里面 一个潜在的高度翻译的目标3我们将测试靶向(局部)补体抑制在 使用一种新的补体抑制剂，名为TT32的人融合蛋白进行实验性PH，该融合蛋白可用于 靶向局部激活的补体信号。

There is convincing evidence for both inflammatory and autoimmune phenomena to be involved in the pathogenesis of PAH. However, both the triggering and the disease sustaining mechanisms remain elusive. Based on emerging evidence in other diseases, including arthritis, kidney disease, and cancer, generated by Co-Investigators on this project, it has become clear that the Complement system, when dysregulated, can become a potent instigator of inflammation-driven tissue injury. Our recently published data demonstrated, we believe for the first time, that the immunoglobulin-driven activation of the complement cascade, specifically its alternative pathway, in the pulmonary perivascular areas is a critical mechanism initiating pro-inflammatory and pro-proliferative processes in experimental hypoxic PH (a form of “sterile inflammation”). We also demonstrated that the activated complement cascade and immunoglobulin G (IgG) deposition are persistent determinants of the disease. The present proposal builds on these findings and comprises both mechanistic and translational arms. In Aim 1 we will evaluate the role of immunoglobulins and complement in initiation of pro-inflammatory processes in PH. In Aim 2 we will evaluate the role of immunoglobulins and complement in the sustained progression of vascular injury and the disease process. In a potentially highly translational Aim 3 we will test the efficacy of targeted (local) complement inhibition in experimental PH using a novel complement inhibitor, human fusion protein termed TT32, which can be used to target local activated complement signaling.