All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin

Qiang Zhang, Douglas E. Kline, Sudin Bhattacharya, Robert B. Crawford, Rory B. Conolly, Russell S. Thomas, Melvin E. Andersen, Norbert E. Kaminski

Research output: Contribution to journalArticle

  • 8 Citations

Abstract

Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR-mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalToxicology and Applied Pharmacology
Volume268
Issue number1
DOIs
StatePublished - Apr 1 2013

Profile

Tetrachlorodibenzodioxin
Cell Differentiation
B-Lymphocytes
Castration
Aryl Hydrocarbon Receptors
Immunoglobulin M
Plasma Cells
Antibody Formation
Berkelium
Callosities
Agaricales
Immunoglobulin Class Switching
Gene Regulatory Networks
Transcription Factor AP-1
Adaptive Immunity
Immunosuppressive Agents
Lipopolysaccharides
Transcription Factors
Ligands
Antibodies

Keywords

  • AhR
  • All-or-none
  • Bach2
  • Bistable
  • Feed-forward
  • TCDD

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. / Zhang, Qiang; Kline, Douglas E.; Bhattacharya, Sudin; Crawford, Robert B.; Conolly, Rory B.; Thomas, Russell S.; Andersen, Melvin E.; Kaminski, Norbert E.

In: Toxicology and Applied Pharmacology, Vol. 268, No. 1, 01.04.2013, p. 17-26.

Research output: Contribution to journalArticle

Zhang, Qiang; Kline, Douglas E.; Bhattacharya, Sudin; Crawford, Robert B.; Conolly, Rory B.; Thomas, Russell S.; Andersen, Melvin E.; Kaminski, Norbert E. / All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In: Toxicology and Applied Pharmacology, Vol. 268, No. 1, 01.04.2013, p. 17-26.

Research output: Contribution to journalArticle

@article{a0e3370cc76c48efbfab2f3e01c2486b,
title = "All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin",
abstract = "Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR-mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation.",
keywords = "AhR, All-or-none, Bach2, Bistable, Feed-forward, TCDD",
author = "Qiang Zhang and Kline, {Douglas E.} and Sudin Bhattacharya and Crawford, {Robert B.} and Conolly, {Rory B.} and Thomas, {Russell S.} and Andersen, {Melvin E.} and Kaminski, {Norbert E.}",
year = "2013",
month = "4",
doi = "10.1016/j.taap.2013.01.015",
volume = "268",
pages = "17--26",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin

AU - Zhang,Qiang

AU - Kline,Douglas E.

AU - Bhattacharya,Sudin

AU - Crawford,Robert B.

AU - Conolly,Rory B.

AU - Thomas,Russell S.

AU - Andersen,Melvin E.

AU - Kaminski,Norbert E.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR-mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation.

AB - Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR-mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation.

KW - AhR

KW - All-or-none

KW - Bach2

KW - Bistable

KW - Feed-forward

KW - TCDD

UR - http://www.scopus.com/inward/record.url?scp=84873906214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873906214&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2013.01.015

DO - 10.1016/j.taap.2013.01.015

M3 - Article

VL - 268

SP - 17

EP - 26

JO - Toxicology and Applied Pharmacology

T2 - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 1

ER -