Cutaneous complement C3 as key driver of pemphigoid disease pathogenesis

补体系统的激活是类天疱疮疾病（PD）中的关键途径，通过PD患者皮肤中补体沉积物的存在以及具有特异性补体缺陷的小鼠对实验性PD的抗性来证明。实验研究证实补体过敏毒素C5 a及其受体C5 aR 1在PD中有很强的作用。另一方面，许多非过敏毒素补体裂解产物的贡献在很大程度上仍然难以捉摸。例如，尽管C3活化产物C3 b及其分解片段iC 3 b和C3 d（g）存款在PD患者的真皮-表皮交界处（DEJ），它们的检测甚至用作重要的诊断标志，但对这些C3调理素对疾病的实际贡献知之甚少。有几个令人信服的理由来更详细地说明C3调理素在PD中的作用：首先，各种抗体类别，包括PD期间产生的自身抗体，激活补体，并可以用C3激活产物促进（自身）抗原的调理作用，形成高度促炎性和免疫原性的“免疫复合物”（IC）。第二，我们的初步数据显示，这样的IC，组成的C3调理IgG结合的PD自身抗原，引起增强炎症反应的粒细胞，关键的皮肤浸润细胞介质在PD。第三，在病情恶化的反馈回路中，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，我们确定了补体C3的局部（非全身）来源对于产生对皮肤局部（自身）抗原的IgG应答是不可或缺的。总的来说，这些观察结果与C3调理素不仅在PD诊断中发挥核心作用，而且实际上直接促进其发展和PD的持续存在，助长炎症，局部C3表达，调理素化和自身抗体产生的有害恶性循环的想法一致。重要的是，由于这种恶性循环围绕皮肤中C3调理素的局部存在和产生，我们预计皮肤C3来源提供有效的，可能局部适用的治疗靶点。因此，在P7中，我们将（i）查明PD中相关的局部皮肤C3来源，（ii）剖析它们对皮肤炎症的影响，反之亦然，（iii）确定局部C3产生对针对PD抗原的体液免疫应答的影响，（iv）探索在临床前PD模型系统中下调C3来源或抑制C3调理素的皮肤活化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PD及其模型系统（Ludwig）的专业知识与补体C3及其多种免疫调节功能（Verschoor）的深入背景相结合。随着C3靶向化合物的出现，接受孤儿药状态及其接近II期临床试验的发展，我们预计C3调节将成为解决PD的有力模式。

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.