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

摘要： 众所周知，TCDD和其他芳烃受体(AhR)配体抑制抗体的产生，但 关于抗体产生减少对通过FCG传递信号的影响的信息很少。 受体(FcgR)FcgRs在几种类型的细胞上表达，并在与Ig G抗体(和它们的 亚型，如IgG1或IgG3)，启动各种效应器功能，包括调理，中和， 凝集、补体激活和抗体依赖的细胞介导的细胞毒(ADCC)的激活。 因此，免疫球蛋白及其亚型在对病原体的免疫应答和自身免疫性疾病中起着关键作用。 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具有潜在的作用 减弱免疫球蛋白介导的效应器功能的配体。因此，这款R15的总体目标是连接相对 AhR配体对免疫球蛋白抗体产生的影响已被很好地描述，而AhR的作用尚未被充分研究 携带FcgR的靶细胞上信号转导的配体。我们将检验AhR配体诱导的假设 抑制免疫球蛋白抗体的产生导致抗体依赖免疫的抑制 回应。这一假设将通过三个具体目标(SA)进行检验。SA1是用来描述这些机制的 通过AhR配体抑制人免疫球蛋白抗体的产生。SA2是评估AhR的直接效果 FcgR刺激的细胞上的配体。SA3是为了评估AhR配体处理的B细胞刺激FcgR- 表达细胞。这些研究的结果将提供重要的信息，通过其机制 TCDD是免疫毒性的，也可能识别其他无毒的AhR配体，这些配体有可能有效 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.