Cutaneous complement C3 as key driver of pemphigoid disease pathogenesis

补体系统的激活是类天疱疮(PD)的关键途径，PD患者皮肤中存在补体沉积，补体特异性缺陷小鼠对实验性PD的抵抗力就是证明。实验研究证实补体过敏性毒素C5a及其受体C5aR1在帕金森病发病中起重要作用。另一方面，许多非过敏性毒素补体裂解产物的作用在很大程度上仍然难以捉摸。例如，尽管C3激活产物C3b及其分解片段iC3b和C3d(G)沉积在PD患者的真皮-表皮交界处(DEJ)，它们的检测甚至可以作为重要的诊断标志，但人们对这些C3调理素在疾病中的实际作用知之甚少。有几个令人信服的理由来更详细地阐述C3调理素在帕金森病中的作用：首先，各种抗体类别，包括帕金森病过程中产生的自身抗体，激活补体，并可以促进(自身)抗原与C3激活产物的调理，形成高度促炎和免疫原性的“免疫复合体”(IC)。第二，我们的初步数据显示，这种由C3调理的免疫球蛋白结合的PD自身抗原组成的IC如何引起粒细胞的炎症反应增强，粒细胞是PD中关键的皮肤浸润性细胞介质。第三，在病情恶化的反馈回路中，正在进行的皮肤炎反应可以进一步增加皮肤局部C3的产生。最后，我们发现局部(非全身性)补体C3来源对于产生皮肤局部(自身)抗原的免疫球蛋白应答是不可或缺的。总之，这些观察结果与C3调色素不仅在帕金森病的诊断中发挥核心作用，而且实际上直接促进帕金森病的发展和帕金森病的永久存在，助长炎症、局部C3表达、调理和自身抗体产生的恶性循环的观点是一致的。重要的是，由于这种恶性循环围绕着皮肤中C3调理素的局部存在和产生，我们预计皮肤C3来源是有效的，可能是局部服从的治疗靶点。因此，在P7中，我们将(I)准确地定位PD中相关的局部皮肤C3来源，(Ii)剖析其对皮肤炎症的影响，反之亦然，(Iii)确定局部C3产生对针对PD抗原的体液免疫反应的影响，(Iv)探索在临床前PD模型系统中下调C3来源或抑制皮肤C3调理素的激活和沉积的化合物的治疗潜力。为了实现这些目标，该项目将临床帕金森病及其模型系统(路德维希)的专业知识与补体C3及其各种免疫调节功能的深入背景相结合(Verschor)。随着C3靶向化合物的出现、孤儿药物的出现以及它们的开发接近第二阶段临床试验，我们预计C3调节将提供一种强大的模式来解决帕金森病。

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.