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Michigan State University

Superfund Research Program

TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach

Project Leader: Norbert E. Kaminski
Grant Number: P42ES004911
Funding Period: 2000-2021

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Project Summary (2013-2021)

Suppression of humoral immunity by the ubiquitous environmental contaminant and prototypical aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorediobenze-p-dioxin (TCDD), has been demonstrated in virtually every animal species tested. Unfortunately, quantification of the effects of AhR ligands on the human immune system, including B cell function, has been sparse. The overall goal of this research is to define the molecular mechanism(s) responsible for AhR agonist-mediated suppression of antibody production by human primary B cells.

Previous results demonstrate that human B cells are sensitive to IgM suppression by TCDD, and exhibit important species-related mechanistic differences compared to mouse B cells. The most striking being that mouse B cells maintain viability under conditions of suboptimal activation (due to weak stimulation or xenobiotic impaired activation), whereas suboptimal activation of human B cells resulted in cell death. These data suggest the existence of a minimal activation threshold that human B cells must attain in order to survive. Based on this critical observation, the research team is testing the hypothesis that suppression of the human primary antibody response by AhR agonists is a multi-event process involving impairment of B cell activation preventing B cells from attaining a minimum activation threshold necessary for their survival. This impaired B cell activation occurs via transcriptionally (DRE)-dependent and -independent mechanisms with AHR polymorphisms dictating B cell sensitivity to AhR agonist-mediated suppression of plasma cell formation.

Five specific goals are testing the central hypothesis:

  1. Determine the magnitude of AhR activation required to impair cellular activation and cell survival
  2. Determine the magnitude of AhR activation required to impair signaling initiated through ligation of CD40 vs. cytokine receptors
  3. Determine the role of epigenetic alterations induced by AhR activation in disruption of the biochemical pathway controlling human primary B cell activation
  4. Define the role of AHR polymorphisms on human B cell sensitivity to AhR-mediated IgM suppression
  5. Determine the role of AhR in TCDD-induced changes in phosphate potential, ATP synthase, and electron transport chain (ETC) activity and define AhR mitochondria localization in human B cells.

Completion of the aforementioned goals will provide critical new mechanistic information on:

  1. The magnitude of AhR activation required to alter B cell function
  2. Whether the B cell impairment exhibits threshold-like properties
  3. The role specific AHR polymorphisms in B cell sensitivity to AhR ligands.

Dioxin and dioxin-like compounds are ubiquitous environmental contaminants present in soil and at all levels of the food chain. Dioxins produce a variety of toxic responses in mammals including wasting syndrome disease, liver toxicity, metabolic syndrome, an increased risk of diabetes and cancer, and especially relevant to this project, immune suppression. This project uses human white blood cells as a model to elucidate the mechanisms responsible for suppressed antibody responses by dioxins.

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