Pathogenicity of IgA-type autoantibodies in pemphigoid disease

类天疱疮病（Pemphigoid diseases，PD）是一种典型的器官特异性自身免疫性疾病。其特征在于针对真皮-表皮连接的结构组分的自身抗体。除了IgG之外，伊加同种型的自身抗体是在PD患者中检测到的第二最丰富的IG同种型。有时，伊加甚至可能是患者体内唯一的自身抗体同种型。与IgG相反，伊加自身抗体的致病相关性从未在体内，特别是在小鼠中令人信服地证明。这方面的一个主要障碍似乎是伊加的受体（与人类炎症细胞上存在的Fc α RI相当）在小鼠中缺失。基于先前的工作，在体外和离体模型PD与纯化和重组伊加自身抗体，我们现在提出了一个项目，旨在建立一个体内模型，重现IgA型自身免疫性水泡病的临床特征，在小鼠。这样的模型是伊加自身抗体介导的疾病的未来研究的基础，并清除了大量的研究问题的途径。在该提案中，我们将解决以下个别假设/研究问题：（i）伊加自身抗体与角质形成细胞的结合诱导促炎介质的释放;（ii）重组和纯化的伊加自身抗体转移到Fc α RI转基因和人源化小鼠中引起炎症和水疱;（iii）通过伊加自身抗体转移诱导水疱取决于促炎介质的释放;和（iv）由伊加自身抗体的转移诱导的水疱对应用于患者的治疗敏感。最终，我们的目标是改善IgA介导的PD患者的治疗选择。伊加自身抗体作为IgA型PD的主要病原体的鉴定对于开发特异性诊断和治疗方案（如ELISA系统和IgA特异性免疫单采方法）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介导的病理可能与这些疾病和PD共有。

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.