Functions of SWAP-70 in B Cell Activation

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DESCRIPTION (provided by the applicant): Signaling pathways that activate B lymphocytes and induce nuclear processes like immunoglobulin (Ig) heavy chain class switching, DNA repair, and DNA replication are incompletely understood. We have identified and characterized a novel phosphoprotein, SWAP-70, that is specifically expressed in activated B cells and in mast cells. SWAP-70 has hallmarks of signaling proteins, e.g. a Rac-specific guanine nucleotide exchange activity, translocates between cytoplasm and nucleus, interacts with DNA repair proteins in the nucleus, and associates with the B cell antigen receptor. Our preliminary analysis of a mouse deficient in SWAP-70-/- indicates a requirement for SWAP-70 in CD4O/IL-4R-triggered proliferation and Ig class switching, especially to the IgE class. Thus, the central hypothesis in this application suggests an important contribution by protein SWAP-70 to B cell activation, especially through the CD40 pathway. The specific aims of this application are to understand (1) the cellular role of SWAP-70 in B cell proliferation and Ig class switching; and (2) the function and mechanism of SWAP-70 specifically in CD40 and IL-4 signaling. B cell activation is key to the immune response and, if improperly controlled, at the heart of several human immune system diseases. Therefore, the analysis of SWAP-70 in B cell activation is likely to help in our understanding of normal B cell function as well as of immune deficiencies, B cell malignancies, autoimmunity, and allergy.