Cutaneous complement C3 as key driver of pemphigoid disease pathogenesis

皮肤补体 C3 是类天疱疮疾病发病机制的关键驱动因素

• 批准号: 279207570
• 负责人: Professor Dr. Ralf Joachim Ludwig
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/279207570?language=en
• 关键词: Cutaneous; complement; C3; key; driver

Activation of the complement system is a key pathway in pemphigoid diseases (PD), evidenced by presence of complement deposits in the skin of PD patients and the resistance of mice with specific complement deficiencies to experimental PD. Experimental studies confirmed a strong contribution of complement anaphylatoxin C5a and its receptor C5aR1 in PD. On the other hand, the contribution of many non-anaphylatoxin complement cleavage products remains largely elusive. For instance, even though the C3 activation product C3b and its breakdown fragments iC3b and C3d(g) deposit at the dermal-epidermal junction (DEJ) in PD patients, their detection even serving as important diagnostic hallmark, little is known about the actual contribution of these C3 opsonins to the disease. There are several compelling reasons to address the role of C3 opsonins in PD in greater detail: first, various antibody classes, including autoantibodies arising during PD, activate complement and can promote opsonization of (auto)antigens with C3 activation products, forming highly proinflammatory and immunogenic “immune complexes” (IC). Second, our preliminary data show how such IC, consisting of C3 opsonized IgG-bound PD autoantigens, provoke an enhanced inflammatory response of granulocytes, key skin-infiltrating cellular mediators in PD. Third, in a condition-worsening feedback loop, ongoing cutaneous inflammatory responses can further increase local C3 production in the skin. Finally, we identified that local (non-systemic) sources of complement C3 are indispensable for the generation of IgG responses to skin-localized (auto)antigens. Collectively, these observations are consistent with the idea that C3 opsonins play a central role not only in PD diagnosis, but actually directly contribute to its development and to the perpetuation of PD, fueling a deleterious vicious cycle of inflammation, local C3 expression, opsonization and autoantibody production. Importantly, since this vicious cycle revolves around local presence and production of C3 opsonins in the skin, we anticipate that cutaneous C3 sources present potent, possibly topically amenable, therapeutic targets. In P7, we will therefore (i) pinpoint relevant local cutaneous C3 sources in PD, (ii) dissect their impact on skin inflammation and vice versa, (iii) determine the impact of local C3 production on the humoral immune response towards PD antigens, (iv) explore the therapeutic potential of compounds that downregulate C3 sources or inhibit dermal activation and deposition of C3 opsonins in preclinical PD model systems. To achieve these goals, this project pairs expertise in clinical PD and its model systems (Ludwig) with in-depth background on complement C3 and its diverse immune-regulatory functions (Verschoor). With the advent of C3-targeting compounds, receiving orphan drug status and their development approaching phase II clinical trials, we anticipate that C3-modulation will present a powerful mode to address PD.

完成系统的激活是Pemphigoid疾病（PD）的关键途径，可以通过PD患者皮肤中的补体沉积物和具有特定补体缺乏症的小鼠的耐药性证明。实验研究证实了补体过敏毒素C5A及其受体C5AR1在PD中做出了强烈的贡献。另一方面，许多非氨基毒素补体裂解产品的贡献基本上难以捉摸。例如，即使C3激活产物C3B及其分解片段IC3B和C3D（G）沉积在PD患者中的皮肤表皮连接（DEJ），但它们的检测甚至是重要的诊断标志，对这些C3副本对疾病的实际贡献而言，对这些诊断的贡献知之甚少。有几个令人信服的理由可以更详细地解决C3 opsonins在PD中的作用：首先，各种抗体类别，包括在PD期间引起的自身抗体，激活完成，并可以促进具有C3激活产物（自动）抗原的调子化，形成高度促炎和免疫性的“免疫机构”（IC）（IC）。其次，我们的初步数据表明，该IC（由C3打开IgG结合的PD自动抗原组成，引起了粒细胞的炎症反应增强，PD中的关键皮肤浸润细胞介体。第三，在较有条件的反馈循环中，持续的皮肤炎症反应可以进一步增加皮肤中局部C3的产生。最后，我们确定了C3的局部（非系统性）完成源对于生成对皮肤钙化（自动）抗原的IgG反应是必不可少的。总的来说，这些观察结果与C3 opsonins不仅在PD诊断中发挥着核心作用，而且实际上直接有助于其发育和PD的持续性，从而促进了有害的炎症，局部C3表达，调子式化和自身抗体的产生。重要的是，由于这种恶性循环围绕皮肤中C3 opsonin的局部存在和产生，因此我们预计皮肤C3来源具有潜力，可能是局部性的，可及时的治疗靶标。 In P7, we will therefore (i) pinpoint relevant local cutaneous C3 sources in PD, (ii) dissect their impact on skin infection and vice versa, (iii) determine the impact of local C3 production On the humoral immunoresponse towards PD antigens, (iv) explore the therapeutic potential of compounds that downregulate C3 sources or inhibit dermal activation and deposition of C3 opsonins in preclinical PD模型系统。为了实现这些目标，该项目在临床PD及其模型系统（Ludwig）方面的专业知识与完整C3的深入背景及其多样化的免疫调节功能（Verschoor）配对。随着C3靶向化合物的冒险，接受孤儿药物状况及其接近II期临床试验的发育，我们预计C3调整将具有强大的方式来解决PD。