The role of complement in mucous membrane pemphigoid

补体在粘膜类天疱疮中的作用

• 批准号: 417348511
• 负责人: Professor Dr. Ralf Joachim Ludwig
• 金额: --
• 依托单位: Lübecker Institut für Experimentelle Dermatologie (LIED)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417348511?language=en
• 关键词: role; complement; mucous; membrane; pemphigoid

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.

粘膜螺旋体（MMP）是一种免疫性疾病，具有针对皮肤表皮连接（DEJ）（DEJ）和主要粘膜参与成分的自身抗体。虽然鉴定靶抗原在分子上改善了MMP的诊断，但该疾病的治疗仍然受到挑战。更具体地说，（i）仅进行了三项受控的治疗试验，（ii）对严重疾病患者的免疫抑制的临床反应，尤其是眼病变，较差，并且（iii）结膜纤维化是不可逆的，与其他pemphigoid疾病相反，在治疗时会延迟或造成其他造成治疗的损害。因此，到目前为止，对MMP的更具体，更安全的治疗方法尚未满足。为了开发新的治疗选择，基于对MMP发病机理的详细了解，我们最近在该模型中开发了临床前的MMP，这是人类疾病的主要免疫病理和临床特征，包括皮肤上的病变，口腔和结膜和结膜粘膜中。本文中，我们注意到临床MMP表现取决于激活FC Gamma受体（FCR）和C5AR1，表明C5A/C5AR1轴的至关重要。为了更好地了解C5对MMP发病机理的贡献，我们在这里将解决采用MMP鼠标模型的以下开放研究问题：（i）C5A（II）C5AR1表达的动力学和细胞来源（ii）表达，（iii）C5A/C5AR1相互作用如何驱动MMP发病机制的c5 clage C5 cleage and C5 Clage and cleage and and and and cleaction and（v） MMP上的化合物。为此，我们将在几个补体报道和缺陷的小鼠中采用新开发的MMP小鼠模型，并使用已建立的药物抑制剂来阻止已知形成C5-旋转酶的特定途径。最终，我们将详细了解MMP中C5A/C5AR1轴的贡献，该轴将确定允许在MMP中进行相对特定干预的治疗靶标。