Investigation of AhR Ligands on FcGamma Receptor Signaling: Consequences of Antibody Suppression

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ABSTRACT: It is well known that TCDD and other aryl hydrocarbon receptor (AhR) ligands suppress antibody production but there is little information about the consequences of decreased antibody production on signaling through Fcg receptors (FcgR). FcgRs are expressed on several cell types and upon being bound by IgG antibodies (and their subtypes, such as IgG1 or IgG3), initiate various effector functions including opsonization, neutralization, agglutination, complement activation, and activation of antibody-dependent cell-mediated cytotoxicity (ADCC). Thus, IgG and its subtypes play critical roles in the immune response to pathogens and in autoimmune diseases. Since TCDD and other AhR ligands have been shown to suppress IgG antibody levels, there is potential for AhR ligands to attenuate IgG-mediated effector function. Thus, the overall goal of this R15 is to connect the relatively well-characterized effects of AhR ligands on IgG antibody production with the understudied effects of AhR ligands on signaling on target cells bearing FcgR. We will test the hypothesis that AhR ligand-induced suppression of IgG antibody production leads to suppression of antibody-dependent immune responses. The hypothesis will be tested with three specific aims (SAs). SA1 is to characterize the mechanisms by which AhR ligands suppress human IgG antibody production. SA2 is to evaluate the direct effect of AhR ligands on FcgR-stimulated cells. SA3 is to evaluate the effect of AhR ligand-treated B cells to stimulate FcgR- expressing cells. Results from these studies will provide important information on the mechanism by which TCDD is immunotoxic and might also identify other non-toxic AhR ligands that have the potential to be effective therapies for autoimmune diseases.