TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach
Suppression of humoral immunity by the ubiquitous environmental contaminant and prototypical aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodiobenzo-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.
Results from the current funding period 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 cell must attain in order to survive. Based on this critical observation, we will test the hypothesis: Suppression of the human primary antibody response by AhR agonists is a multi-event process involving impairment of B cell activation, which in turn impedes attainment of a minimum activation threshold requisite for B cell survival. The magnitude of this impediment in activation strength is dictated by AHR polymorphisms and determines B cell sensitivity to AhR agonist-mediated suppression of plasma cell formation. Four specific aims (SA) will test the central hypothesis. SA1 is to determine the magnitude of AhR activation required to impair cellular activation and cell survival. SA2 is to determine the magnitude of AhR activation required to impair signaling initiated through ligation of CD40 vs. cytokine receptors. SA3 is to determine the role of epigenetic alterations induced by AhR activation in disruption of the biochemical pathway controlling human primary B cell activation. SA4 is to define the role of AHR polymorphisms on human B cell sensitivity to AhR-mediated IgM suppression.
Completion of the aforementioned specific aims will provide critical new mechanistic information on:
- the magnitude of AhR activation required to suppress human B cell function
- whether the B cell impairment exhibits threshold-like properties
- the role specific AHR polymorphisms in human B cell play in determine sensitivity to AhR ligands, which if understood could be used as a biomarker of susceptibility (or lack of) to humoral immune suppression by dioxin-like compounds