Characterization of IgA- and IgE- mediated pathogenicity using a humanized pemphigus mouse model

• Applicant: Dr. Christoph Thomas Ellebrecht
• Subject Area: Dermatology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221334494

Pemphigus is a group of severe autoimmune blistering skin diseases characterized by antibodies to desmosomal proteins known as desmogleins (Dsg). Several clinical subtypes of pemphigus have been described, many of which are characterized not only by IgG binding to keratinocytes and blister formation but also by deposition of IgA or IgE and subsequent neutrophil and/or eosinophil infiltration. Although the role of the variable region of anti-Dsg antibodies has been characterized extensively, there are few data concerning different autoantibody isotypes in pemphigus and their influence on pathogenicity and response to therapy. Evaluation of IgA and IgE in the pathogenesis of pemphigus is highly desirable to reveal new therapeutic targets and more specific therapeutic approaches in IgA- /IgE- mediated skin diseases. We hypothesize that depending on the capability of the variable region of the autoantibodies to induce blisters (termed pathogenic), IgA/IgE can produce different clinical phenotypes of pemphigus and that these phenotypes can be specifically treated. Due to the innovative technique of phage display, we are able to produce full length monoclonal anti-Dsg-IgA and -IgE with pathogenic or nonpathogenic variable regions. We will assess our hypotheses 1) by producing monoclonal pathogenic and nonpathogenic IgA and IgE from pemphigus patients and 2) by characterizing their pathogenicity and effector function in a novel humanized mouse model with murine leukocytes expressing human Fcalpha/Fcepsilon receptors. Additionally, pathogenicity of IgA and IgE will be evaluated 3) by treatment with either dapsone or omalizumab to inhibit the Fc-mediated effector function of IgA or IgE, respectively. The knowledge that will be gained from the proposed studies is significant, since it enables a deeper understanding of the pathophysiology of pemphigus, rational treatment strategies, and a major advancement in technology for evaluating immunobullous diseases in general.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Aimee Payne