The Asthma, Allergic, and Immunologic Diseases Cooperative Research Center of the University of Alabama at Birmingham (UAB) is a multidisciplinary effort, involving faculty and staff of the clinical Departments of Medicine and Pediatrics, and the basic science Department of Microbiology. The primary focus is the elucidation of pathogenetic mechanisms operative in allerigc diseases of immune function. The Demonstration and Education Research component will focus on means to increase the effectiveness of educational interventions in improving asthma management. The BioMedical Research Component is composed of four integrated research projects designed to pursue experimental leads gained in earlier studies. As most of the investigators are actively involved in the care of patients with immunologic diseases, the program provides a working interface between basic and applied immunology. Atopic diseases result from the release of mediators of inflammation, a process associated with aggregation of high affinity receptors for lgE on the surface of mast cells (Fc-epsilon-RI). Project 1 will focus on phospholipase C-gamma1 isozymes that have been recently shown to be activated following Fc-epsilon-RI aggregation. Mechanisms of substrate hydrolysis and signal transduction will be studied. Project 2 will examine the hypothesis that susceptibility to atopic disease results from premature activation of the IgE response in the fetus. The composition of the IgE antibody repertoire will be determined as a function of ontogeny. Infants at high risk for atopic disease will be identified through recruitment of pregnant women in our allergy clinics and their cord blood IgE repertoire will be examined. Project 3 will focus on analysis of the molecular mechanisms that contribute to the immature phenotype of sIgA+ cells that are seen patients with IgA deficiency (IgAD) and in normal newborns. These cells will be purified by a newly developed combination of sorting techniques for analysis of the extent of C-mu deletion, a prerequisite for class switch recombination. The cells will also be examined for their responses to cytokines and to purified mixtures of T and B cell subpopulations. In order to gain further insight into host factors that can compensate for lgA deficiency, a mutant mouse model lacking lgA will be created. Abnormalities in thymic development may contribute to both atopy and lgA deficiency. In Project 4, the mechanism by which abnormal expression of the fas apoptosis antigen contributes to the loss of T cell tolerance in lpr mice will be studied.
