PROJECT SUMMARY There is a fundamental gap in our understanding of the pathogenic mechanisms of Bullous pemphigoid (BP), an autoimmune blistering disease. Thus, standard treatment consists of high dose immunosuppression, which is associated with significant morbidity and mortality in the elderly population typically affected by BP. Our long- term goal is to identify the cellular and molecular events that lead to the development and propagation of cutaneous autoimmunity so that better therapies can be developed. The objective of this proposal is to develop an active mouse model of BP that recapitulates human disease by eliciting both IgE and IgG autoantibodies BP. Although BP is one of a growing number of autoimmune diseases characterized by pathogenic IgE autoantibodies, and these IgE antibodies are critical for recapitulation of human disease in passive transfer models of disease, there is no active disease model that includes both an IgG and an IgE response to the BP autoantigen. Our hypothesis that the route of antigen exposure is critical for the development of an IgE autoantibody response. The rationale for the proposed research is generation of a robust active model of BP will address the shortcomings of current passive models and will facilitate studies of the basic mechanisms of BP and other instances of IgE-mediated autoimmunity. Guided by our preliminary data, this hypothesis will be tested by pursuing the following specific aim: To identify the immunization regimen that generates mBP180-specific IgE and IgG and cutaneous lesions consistent with BP. Mice will be immunized with the murine homolog of the BP autoantigen to determined how the route of antigen exposure influences the form and nature of the autoantibody response. At regular intervals, the extent of skin disease, the level of circulating antibodies, and the cutaneous immune cell populations will be assessed. These studies are relevant to the NIH’s mission aimed at enhancing health, lengthening life and reducing illness, and to that of the NIAID to better understand the immunologic basis of disease, including developing a greater understanding of fundamental immunologic principles underlying disease onset and progression and developing improved animal models of disease. This approach is innovative because there are currently no established mouse models of human autoimmune diseases that feature IgE. The proposed studies are significant because they will advance and expand our understanding of the basic mechanisms of cutaneous autoimmunity and will lay the groundwork for future studies aimed at identifying the cellular and molecular mechanisms of disease that can be targeted therapeutically.