INDUCTION OF IG C EPSILON & C GAMMA 1 BY IL4 & CD40L

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After immunization or infection, B cells undergo immunoglobulin (Ig) class switching, which results in expression of a new heavy chain constant region (C/H) region gene. Class switching allows the humoral immune response to adaptively respond to a variety of different infectious organisms to produce the best antibody for each pathogen. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse a model system. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse as a model system. Both IgG1 and IgE are produced in response to T dependent antigens, although IgG1 in much greater abundance that IgE. IgG1 in effective against bacterial, viral and nematode infections due to its ability to active complement and to bind to FcRgammaIII on macrophages, neutrophils, mast cells and NK cells. IgE helps to eliminate parasitic helminths, although it does not appear to be essential for this immune response and in industrial societies is generally more dangerous than protective, as it causes allergy, including asthma. Thus, the ability to increase IgG1 and decrease IgE responses would be useful medically. Numerous studies have established that transcription of the C/H gene to which cells will switch is induced prior to switching by cytokines and B cell activators, and that this transcription is required for class switching. This proposal is to investigate the mechanism of regulation of germline gamma1 and epsilon transcription by cytokines and B cell activators known to regulate class switching to IgG1 and IgE. The proposal will specifically investigate and compare the regulation of the germline gamma1 and epsilon transcripts by three transcription factors/families which are involved in induction of transcription by IL-4 and CD40 signaling: Stat6, NF-kappaB/Rel proteins, and b-Zip proteins. We have shown that Stat6 and NF-kappaB directly bind each other and have evidence suggesting this is the mechanism whereby IL-4 and CD40 signaling synergistically induce transcription. This proposal will directly address whether this binding is necessary for their synergy and analyze the mechanism of their interaction. A b-Zip binding site which binds Ap-1 is also required for the ability of Stat6 to induce transcription, but the requirement for the Ap-1 binding site is not understood. We will investigate whether this requirement is due to the inability of Stat6 to bind to chromatin in vivo in the absence of AP-1. The promoters for the gamma1 and epsilon germline transcripts have similar binding sites for Stat6, NF-kappaB and AP-1 (or for C/EBP), but these sites are differentially arranged. We will determine if it is the differential arrangement and/or different binding proteins at the b-Zip element which regulates their different responses to IL-4 and B cell activators.