The role of complement in mucous membrane pemphigoid

粘膜类天疱疮（MMP）是一种免疫大疱性疾病，其自身抗体对抗真皮-表皮交界处（DEJ）的成分，主要累及粘膜。虽然分子上靶抗原的鉴定改善了MMP的诊断，但该疾病的治疗仍然具有挑战性。更具体地说，(i)只进行了三个对照治疗试验，（ii）严重疾病患者，特别是眼部病变患者对免疫抑制的临床反应很差，（iii）结膜纤维化是不可逆的，与其他类天疱疮疾病相比，如果治疗延迟或无效，会造成永久性损害。因此，对更具体和更安全的MMP治疗方法的高度医疗需求迄今尚未得到满足。为了在详细了解MMP发病机制的基础上开发新的治疗方案，我们最近开发了一种临床前MMP模型，在该模型中，抗层粘连蛋白332 （MMP中定义明确的自身抗原）抗体转移到成年小鼠体内诱导疾病。在该模型中，概括了人类疾病的主要免疫病理和临床特征，包括皮肤、口腔和结膜粘膜的病变。在此，我们注意到临床MMP表现依赖于激活Fc γ受体（FcR）和C5aR1，这表明C5a/C5aR1轴起着至关重要的作用。为了更好地理解C5对MMP发病机制的贡献，我们将利用MMP小鼠模型解决以下开放性研究问题：(i) C5a的动力学和细胞来源(s); (ii) C5aR1表达；（iii） C5a/C5aR1相互作用如何驱动MMP发病机制；（iv）哪些途径导致C5切割；(v)补体靶向化合物对MMP的影响。为此，我们将在几种补体报告基因缺失和缺陷小鼠中使用新开发的MMP小鼠模型，并使用已建立的药理学抑制剂来阻断已知形成c5转化酶的特定途径。最终，我们将详细了解C5a/ c5ar1轴在MMP中的作用，这将确定允许对MMP进行相对特异性干预的治疗靶点。

Mucous membrane pemphigoid (MMP) is an immunobullous disease with autoantibodies against components of the dermal-epidermal junction (DEJ) and predominant mucosal involvement. While the identification of the target antigens on the molecular has improved the diagnosis of MMP, treatment of the disease remains challenging. More specifically, (i) only three controlled therapeutic trials have been conducted, (ii) clinical response to immunosuppression in patients with severe disease, in particular with ocular lesions, is poor, and (iii) conjunctival fibrosis is irreversible and, in contrast to other pemphigoid diseases, causes permanent damage when treatment is delayed or ineffective. Hence, there is a so far unmet high medical need for more specific and safer treatments for MMP. In order to develop novel treatment options, which are based on a detailed understanding of MMP pathogenesis, we recently developed a pre-clinical MMP model, in which the disease is induced by transfer of anti-laminin 332 (a well-defined autoantigen in MMP) antibodies into adult mice. In this model, major immunopathological and clinical characteristics of the human disease including lesions on the skin and in the oral and conjunctival mucosa are recapitulated. Herein, we noted that clinical MMP manifestation depends on activating Fc gamma receptors (FcR) and the C5aR1, indicating a crucial contribution of the C5a/C5aR1-axis. To better understand the contribution of the C5 to MMP pathogenesis, we here, will address the following open research questions employing the MMP mouse model: (i) the kinetics and cellular source(s) of C5a (ii) C5aR1 expression, (iii) how C5a/C5aR1 interaction drives MMP pathogenesis, (iv) which pathways lead to C5 cleavage, and (v) the impact of complement-targeting compounds on MMP. For this purpose, we will employ the newly developed MMP mouse model in several complement reporter- and deficient mice, as well use established pharmacological inhibitors to block specific pathways known to form a C5-convertase. Ultimately, we will gain detailed insights into the contribution of the C5a/C5aR1-axis in MMP, which will identify therapeutic targets that allow a relatively specific intervention in MMP.