The aryl hydrocarbon receptor differentially modulates the expression profile of antibody isotypes in a human B-cell line.

in Toxicological sciences : an official journal of the Society of Toxicology by Mili S Bhakta-Yadav, Kaulini Burra, Nasser Alhamdan, Clayton P Allex-Buckner, Courtney E W Sulentic

TLDR

  • This study looked at how a chemical called TCDD affects the way our bodies make antibodies. They used a special type of cell called a B-cell and exposed it to different chemicals that can activate or block the chemical's effects. They found that the chemical can affect the way our bodies make certain types of antibodies, which could have implications for our health.

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high affinity ligand for the aryl hydrocarbon receptor (AhR). In animal models, AhR activation by TCDD generally inhibits antibody secretion. However, it is less clear if this translates to human antibody production. Using a human Burkitt lymphoma B-cell line (CL-01) that can be stimulated to secrete Ig and undergo class switch recombination to other Ig isotypes, the current study evaluated the effects of AhR activation or antagonism on the human Ig isotypic expression profile with CD40L+IL-4 stimulation. Our results suggest that AhR agonists (TCDD and indirubin) have little to no effect on IgM or IgA secretion, which were also not induced with stimulation. However, AhR activation significantly inhibited stimulation-induced IgG secretion, an effect reversed by the AhR antagonist CH223191. Evaluation of Ig heavy chain (IgH) constant region gene expression (ie Cμ, Cγ1-4, Cα1-2, and Cε that encode for IgM, IgG1-4, IgA1-2, and IgE, respectively) demonstrated differential effects. While Cμ and Cα2 transcripts were unaffected by stimulation or AhR agonists, AhR activation significantly inhibited stimulation-induced Cγ2-4 and Cε mRNA transcripts, which was reversed by AhR antagonism. Notably, AhR antagonism in the absence of exogenous AhR ligands significantly increased IgG and IgA secretion as well as the expression of Cγ2-4 and Cε. These results suggest that modulation of AhR activity differentially alters the IgH isotypic expression profile and antibody secretion that may be partly dependent on cellular stimulation. Since a variety of chemicals from anthropogenic, industrial, pharmaceutical, dietary, and bacterial sources bind the AhR, the ability of environmental exposures to alter AhR activity (ie activate or inhibit) may have a direct influence on immune function and antibody-relevant disease conditions.

Overview

  • The study evaluates the effects of AhR activation or antagonism on the human Ig isotypic expression profile with CD40L+IL-4 stimulation using a human Burkitt lymphoma B-cell line (CL-01).
  • The primary objective of the study is to investigate the differential effects of AhR activation on the IgH isotypic expression profile and antibody secretion that may be partly dependent on cellular stimulation.

Comparative Analysis & Findings

  • AhR agonists (TCDD and indirubin) have little to no effect on IgM or IgA secretion, which were also not induced with stimulation. However, AhR activation significantly inhibited stimulation-induced IgG secretion, an effect reversed by the AhR antagonist CH223191. Evaluation of Ig heavy chain (IgH) constant region gene expression demonstrated differential effects. While Cμ and Cα2 transcripts were unaffected by stimulation or AhR agonists, AhR activation significantly inhibited stimulation-induced Cγ2-4 and Cε mRNA transcripts, which was reversed by AhR antagonism. Notably, AhR antagonism in the absence of exogenous AhR ligands significantly increased IgG and IgA secretion as well as the expression of Cγ2-4 and Cε.

Implications and Future Directions

  • The study's findings suggest that modulation of AhR activity differentially alters the IgH isotypic expression profile and antibody secretion that may be partly dependent on cellular stimulation. Since a variety of chemicals from anthropogenic, industrial, pharmaceutical, dietary, and bacterial sources bind the AhR, the ability of environmental exposures to alter AhR activity (ie activate or inhibit) may have a direct influence on immune function and antibody-relevant disease conditions. Future research directions could include investigating the effects of AhR activation or antagonism on other immune cell types and disease conditions, as well as exploring the potential therapeutic applications of AhR modulators.
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