Allergic diseases, autoimmune disorders and antibody deficiency syndromes can be viewed as diseases that affect the mechanisms that control B cell activation and antibody production. A molecular understanding of the processes involved in B cell activation and antibody production is essential for accurate diagnosis and therapy of allergic and immune diseases. In this IDCRC we propose to study the mechanism of B cell activation and isotype switching and the molecular basis of two immunodeficiency diseases (MHC Class II deficiency and Wiskott Aldrich syndrome) that affect T cells and impair the capacity of B cells to mount an antigen specific antibody response. For this purpose, we will use recently acquired knowledge of signal transduction and of isotype switching to study B cell activation; we will also construct an experimental model of MHC Class II deficiency and we will attempt to elucidate the molecular defect in Wiskott Aldrich syndrome. Definition of the mechanisms of control of epsilon germ line transcription by IL4 (project #1, F. Alt) and of the mechanisms of IgE isotype switching triggered via CD40 (project #2, R. Geha) will permit a better understanding of allergic diseases. Definition of the mechanisms of B cell activation via surface immunoglobulins (project #3, C. Terhorst) and MHC Class II molecules (project #4, T. Chatila) will provide better understanding of the mechanisms of activation of normal B cells by antigen, antigen specific T cells, and bacterial enterotoxins which are implicated in many diseases including toxic shock syndrome, food poisoning, scarlet fever, and possibly autoimmune diseases. The construction of MHC Class II deficient mice (project #5, L. Glimcher) will provide an invaluable model for the study of a human disease and to explore the implications of the loss of Ia expression on immune function. The prospect for defective activity of the neutral protease calpain to underlie the immune defect in Wiskott Aldrich syndrome will extend the concept first illustrated by adenosine deaminase deficiency that enzymatic defects may result in profound immune dysfunction, (project #6, F. Rosen). An asthma education and demonstration program (project #7, C. Homer) assesses the impact of education of patients and physicians on asthma mortality and morbidity in inner city children. The results of the proposed studies will enhance our understanding of immune function and help devise rational therapeutic interventions for allergic and immunologic diseases.
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