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.

类天疱疮疾病（PD）是典型的器官特异性自身免疫性疾病。它们的特征是针对真皮-表皮交界处的结构成分的自身抗体。除 IgG 外，IgA 同种型自身抗体是 PD 患者中检测到的第二丰富的 Ig 同种型。有时，IgA 甚至可能是患者自身抗体的唯一同种型。与 IgG 相比，IgA 自身抗体的致病相关性从未在体内（特别是在小鼠体内）得到令人信服的证明。实现这一目标的一个主要障碍似乎是，与人类炎症细胞上存在的 Fc α RI 类似，小鼠体内缺少 IgA 受体。基于之前使用纯化和重组 IgA 自身抗体进行 PD 体外和离体模型的工作，我们现在提出了一个项目，旨在建立一个体内模型，重现小鼠 IgA 型自身免疫性水疱疾病的临床特征。这种模型对于 IgA 自身抗体介导的疾病的未来研究至关重要，并为解决大量研究问题扫清了道路。在本提案中，我们将解决以下个别假设/研究问题：（i）IgA 自身抗体与角质形成细胞的结合诱导促炎介质的释放； (ii) 将重组和纯化的 IgA 自身抗体转移到 Fc α RI 转基因和人源化小鼠中会引起炎症和水疱； (iii) IgA自身抗体的转移诱导水疱取决于促炎介质的释放； (iv) IgA 自身抗体转移引起的水疱对患者的治疗敏感。最终我们的目标是改善 IgA 介导的 PD 患者的治疗选择。鉴定 IgA 自身抗体作为 IgA 型 PD 的主要致病因子对于开发特定的诊断和治疗方案（例如 ELISA 系统和 IgA 特异性免疫分离方法）至关重要。这些进展有望对 IgA 型自身免疫性疾病患者有益，因为 IgA 介导的病理学可能与这些疾病和 PD 相同。