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 multievent 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. SAI 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;(1) the magnitude of AhR activation required to suppress human B cell function;(2) whether the B cell impairment exhibits threshold like properties;and (3) 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.

Public Health Relevance

;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, increased risk of cancer, and especially relevant to this project, immune suppression. This project uses human white blood cells to elucidate the mechanisms for suppressed antibody responses by dioxins and makes comparisons to mouse white blood cells, which have been used almost exclusively to predict human immunotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES004911-22A1
Application #
8564225
Study Section
Special Emphasis Panel (ZES1-LWJ-D (SF))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
22
Fiscal Year
2013
Total Cost
$283,597
Indirect Cost
$91,769
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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