Allergic diseases affect 20% of the population and are characterized by predominance of allergen specific Th2 helper cells and IgE antibody. The cytokines IL-4 and 11-13 plays a critical role in the development of Th2 helper cells and synergizes with CD40 ligand (CD40L) to induce IgE isotype switching. In this proposal, three investigators with long standing interest in the molecular mechanisms of allergic diseases join together again to renew their AADCRC, based at Children's' Hospital, with the aim of elucidating the mechanisms of regulation of three key elements in the elements in the development of allergic diseases, namely, Th2 cell development, signals that induce isotype and class switch recombination (CSR). In project #1, based on her previous findings that the transcription factor T-bet dictates the Thl genetic program while the NFAT transcription factors control the production of IL-4, L. Glimcher, proposes to examine the in vivo role of T-bet in allergic airway and skin inflammation in mice and polymorphism of the T-bet gene in human asthma, In addition, she will examine the role of NFAT in CD8 cells and dendritic cell function in the allergic phenotype and the role of IRF4 in cytokine regulation. In Project #2, based on his observation that the human complement regulatory protein C4BP is an activating ligand for CD40, R. Geha will analyze the structural and functional aspects of the C4BPCD40 interaction and will investigate the role of C4BP in B cell maturation, CSR and somatic hypermutation (SHM) in secondary lymphoid follicles of human tonsils. He will also generate C4BP knockout mice to assess and the role of C4BP in B cell activation, CSR, SHM and germinal center formation. In Project #3, F. AIt plans to continue his studies on the molecular basis of CSR. He will build on his long-standing and cutting edge expertise in this field to identify novel DNA elements and molecules that control the process of immunoglobulin isotype switching in vivo using transgenic mice models, and to investigate the mechanism of action of activation induced deaminase (AID) in class switch recombination. The results of the proposed studies have important implications for the development of Th2 cells and for IgE isotype switching in allergic individuals. The fact that the three projects are inter-related at the intellectual, scientific and technologic levels and that the investigators have established long term collaborations among themselves will improve the cost benefit ratio and result in substantial savings in expenditure of time and money.
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