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

摘要： 众所周知，TCDD和其它芳烃受体（AhR）配体抑制抗体产生，但 关于抗体产生减少对通过Fcg的信号传导的影响的信息很少 受体（FcgR）。FcgR在多种细胞类型上表达，并在与IgG抗体（及其抗体）结合后表达 亚型，如IgG 1或IgG 3），启动各种效应子功能，包括调理作用，中和， 凝集、补体激活和抗体依赖性细胞介导的细胞毒性（ADCC）的激活。 因此，IgG及其亚型在对病原体的免疫应答和自身免疫性疾病中起关键作用。 由于TCDD和其他AhR配体已被证明可以抑制IgG抗体水平，因此AhR有可能 配体以减弱IgG介导的效应子功能。因此，该R15的总体目标是连接相对 AhR配体对IgG抗体产生的充分表征的作用， 配体对携带FcgR的靶细胞上的信号传导的影响。我们将检验AhR配体诱导的 IgG抗体产生的抑制导致抗体依赖性免疫抑制 应答该假设将通过三个特定目标（SA）进行检验。SA 1是表征机制 AhR配体通过其抑制人IgG抗体产生。SA2是评价AhR的直接作用 FcgR刺激的细胞上的配体。SA 3是为了评估AhR配体处理的B细胞刺激FcgR的作用。 表达细胞。这些研究的结果将提供重要的信息， TCDD具有免疫毒性，也可能识别出其他可能有效的无毒AhR配体 自身免疫性疾病的治疗方法

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.