Pathogenicity of IgA-type autoantibodies in pemphigoid disease

• Applicants: Professor Dr. Ralf Joachim Ludwig; Professor Dr. Falk Nimmerjahn; Dr. Andreas Recke
• Subject Area: Dermatology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424656607

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.

• DFG Programme: Research Grants