Pathogenicity of IgA-type autoantibodies in pemphigoid disease

类天疱疮是典型的器官特异性自身免疫性疾病。它们的特点是针对真皮-表皮交界处的结构成分产生自身抗体。除免疫球蛋白外，免疫球蛋白A同型自身抗体是帕金森病患者中第二丰富的免疫球蛋白同型。有时，IgA甚至可能是患者中唯一的同型自身抗体。与免疫球蛋白相比，免疫球蛋白A自身抗体的致病相关性从未在活体中得到令人信服的证明，特别是在小鼠身上。这方面的一个主要障碍似乎是，小鼠体内缺少一种与人类炎症细胞上存在的FcαRI类似的IgA受体。在先前用纯化的和重组的IgA自身抗体建立帕金森病体外和体外模型的基础上，我们现在提出一个项目，旨在建立一个体内模型，再现小鼠的IgA型自身免疫性水泡病的临床特征。这样的模型为未来对IgA自身抗体介导的疾病的研究奠定了基础，并为解决大量研究问题扫清了道路。在这项建议中，我们将解决下列个别假设/研究问题：(I)IgA自身抗体与角质形成细胞结合可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FcαRI转基因小鼠和人源化小鼠体内会引起炎症和起泡；(Iii)转移IgA自身抗体引起水泡依赖于促炎介质的释放；以及(Iv)转移IgA自身抗体引起的水泡对患者应用的治疗敏感。最终，我们的目标是改善免疫球蛋白A介导的帕金森病患者的治疗选择。确定IgA自身抗体是IgA型帕金森病的主要致病因素，对于开发特定的诊断和治疗方案，如ELISA系统和IgA特异性免疫分离方法，是至关重要的。这些进展有望在总体上有益于IgA型自身免疫性疾病患者，因为IgA介导的病理可能与这些患者和帕金森病患者相同。

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.