Interactions of lgC4 & lgE anti-Dsg1 Autoantibodies in Endemic Pemphigus Foliaceu

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DESCRIPTION (provided by applicant): The P.I. has recently entered the research field of cutaneous autoimmunity. His career development plan is designed to secure advanced training in this field and prepare him to become an independent investigator under the guidance of his mentor, Dr. L.A. Diaz, who is internationally recognized as a leader in the field of skin diseases. To enhance the training, the program has enlisted the expertise of an advisory committee that consists of established investigators with expertise in the field of cutaneous biology, autoimmunity and allergy, and biostatistics for the scientific and career advice. The P.I. have been studying the mechanism of the development of auto antibodies in endemic [Fogo Selvagem (FS)] and non-endemic pemphigus foliaceus (PF) and pemphigus vulgaris (PV). He is focusing on the initiation and development of pathogenic anti- desmoglein 1 (Dsg1) auto antibodies that are found in these patients. This grant explores the interaction of self-reactive IgE antibodies and pathogenic lgG4 auto antibodies in FS. Recent work in our laboratory demonstrated that FS patients have significantly higher levels of anti-Dsgl IgE antibodies compared to healthy controls. We hypothesize that the lgG4 and IgE anti-Dsgl autoantibody responses in FS are triggered by the same environmental antigen ("allergen"). The candidate's immediate research plan is to provide evidence that the IgE and lgG4 autoantibody response in FS is relevant to the pathogenesis of the disease. Aim 1 will focus on the interactions of IgE and lgG4 anti-Dsgl response in FS patients and healthy individuals from endemic areas of FS. In Aim 2, we will generate anti-Dsgl IgE monoclonal antibodies to study their V gene usage, and analyze whether there is any genetic relationship between anti-Dsgl lgG4 and IgE auto antibodies in the same FS patients through their "clonal signature". In Aim 3, we will determine the pathogen city of anti-Dsgl IgE antibodies by the passive transfer mouse model. The successful conclusion of this project will shed light on our understanding of the mechanism of etiology and pathogenesis of FS, as well as other human cutaneous diseases. Additionally, this K01 Award will promote the career advancement of the applicant and help him to achieve research independence.