Pathogenicity of IgA-type autoantibodies in pemphigoid disease

IgA 型自身抗体在类天疱疮疾病中的致病性

• 批准号: 424656607
• 负责人: Professor Dr. Ralf Joachim Ludwig
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/424656607?language=en
• 关键词: Pathogenicity; IgA; type; autoantibodies; pemphigoid

Pemphigoid diseases (PD) are prototypic organ-specific autoimmune diseases. They are characterized by autoantibodies directed against structural components of the dermal-epidermal junction. Besides IgG, autoantibodies of the IgA isotype are the second most abundant Ig isotype detected in PD patients. Sometimes, IgA may be even the only isotype of autoantibodies in patients. In contrast to IgG, the pathogenic relevance of IgA autoantibodies has never been convincingly demonstrated in vivo, specifically, in mice. A major obstacle for this appears to be that a receptor for IgA, comparable to Fc alpha RI present on inflammatory cells in humans, is missing in mice. Based upon prior work with in vitro and ex vivo models of PD with purified and recombinant IgA autoantibodies, we now propose a project which aims at establishing an in vivo model that reproduces the clinical features of IgA-type autoimmune blistering diseases in mice. Such a model is fundamental for future research on IgA autoantibody-mediated diseases and clears the path to approach a large number of research questions. Within this proposal we will address the following individual hypotheses/research questions: (i) binding of IgA autoantibodies to keratinocytes induces the release of pro-inflammatory mediators; (ii) transfer of recombinant and purified IgA autoantibodies into Fc alpha RI-transgenic and humanized mice causes inflammation and blistering; (iii) induction of blistering by transfer of IgA autoantibodies depends on the release of pro-inflammatory mediators; and (iv) blistering induced by transfer of IgA autoantibodies is sensitive to treatments applied in patients. Ultimately we aim to improve the treatment options for patients with IgA-mediated PD. Identification of IgA autoantibodies as primary pathogenic agents in IgA-type PD is fundamental for the development of specific diagnostic and treatment options, such as ELISA systems and IgA-specific immunoapheresis methods. These developments will hopefully be beneficial for patients with IgA-type autoimmune diseases in general, because IgA-mediated pathology may be shared with these and PD.

雌性疾病（PD）是原型器官特异性自身免疫性疾病。它们的特征是针对皮肤表皮连接的结构成分的自身抗体。除IgG外，IgA同种型的自身抗体是PD患者中检测到的第二大大量Ig同型。有时，IgA甚至可能是患者自身抗体的唯一同种型。与IgG相反，IgA自身抗体的致病相关性从未在体内令人信服地证明，特别是在小鼠中。这样的主要障碍似乎是小鼠缺少IgA的受体，与人类炎症细胞上存在的FCαRI相当。基于先前使用纯化和重组IgA自身抗体的PD体外和离体模型的工作，我们现在提出一个项目，旨在建立一个体内模型，该模型重现小鼠中IGA型自身免疫性症状的临床特征。这种模型对于未来对IGA自身抗体介导的疾病的研究至关重要，并清除了解决大量研究问题的途径。在此提案中，我们将解决以下个体假设/研究问题：（i）IgA自身抗体与角质形成细胞的结合会诱导促炎性介体的释放； （ii）将重组和纯化的IGA自身抗体转移到Fcαri-Transgenic和人源性小鼠中会引起炎症和起泡； （iii）通过IGA自身抗体转移来诱导起泡，取决于促炎性介体的释放； （iv）通过IGA自身抗体转移引起的起泡对患者的治疗敏感。最终，我们旨在改善IGA介导的PD患者的治疗选择。 IgA自身抗体作为IgA型PD中主要致病剂的鉴定对于开发特定的诊断和治疗方案的发展至关重要，例如ELISA系统和IGA特异性免疫术方法。这些事态发展将对IgA型自身免疫性疾病的患者有益，因为IgA介导的病理可能会与这些疾病和PD共享。