The role of complement in mucous membrane pemphigoid

粘膜类天疱疮是一种免疫性疾病，具有针对真皮-表皮交界处(DEJ)成分的自身抗体，并以粘膜受累为主。虽然分子上靶抗原的识别提高了对多发性骨髓瘤的诊断，但该病的治疗仍然具有挑战性。更具体地说，(I)只进行了三项对照治疗试验，(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转的，与其他类天疱疮疾病不同，当治疗延迟或无效时，会造成永久性损害。因此，到目前为止，对于更特异和更安全的治疗基质金属蛋白酶有很高的医学需求，尚未得到满足。为了开发基于对MMP发病机制的详细了解的新的治疗方案，我们最近开发了一种临床前的MMP模型，在该模型中，通过将抗层粘连蛋白332(一种明确定义的自身抗原)抗体转移到成年小鼠体内来诱导疾病。在这个模型中，总结了人类疾病的主要免疫病理和临床特征，包括皮肤以及口腔和结膜粘膜的损害。在此，我们注意到临床表现依赖于激活Fcγ受体(FcR)和C5aR1，这表明C5a/C5aR1轴起着至关重要的作用。为了更好地了解C5在基质金属蛋白酶发病机制中的作用，我们将利用基质金属蛋白酶小鼠模型来解决以下开放的研究问题：(I)C5a(Ii)C5aR1表达的动力学和细胞来源(S)，(Iii)C5a/C5aR1相互作用如何驱动基质金属蛋白酶的发病，(Iv)哪些途径导致C5裂解，以及(V)补体靶向化合物对基质金属蛋白酶的影响。为此，我们将在几种补体报告和缺乏补体的小鼠中使用新开发的MMP鼠模型，以及使用现有的药物抑制剂来阻断已知的形成C5转换酶的特定途径。最终，我们将获得对C5a/C5aR1轴在基质金属蛋白酶中作用的详细见解，这将确定允许对基质金属蛋白酶进行相对特定干预的治疗靶点。

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.