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

Journal Article · Mon Apr 01 04:00:00 EDT 2013 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2013.01.015· OSTI ID:22285255

Zhang, Qiang ^[1]; Kline, Douglas E. ^[2]; Bhattacharya, Sudin ^[1]; Crawford, Robert B. ^[2]; Conolly, Rory B. ^[3]; Thomas, Russell S.; Andersen, Melvin E. ^[1]

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1. Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, RTP, NC 27709 (United States)
2. Department of Pharmacology and Toxicology and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States)
3. Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC 27711 (United States)

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. - Highlights: ► TCDD suppresses B cell differentiation stimulated by LPS in an all-or-none mode. ► TCDD reduces the fraction of IgM-secreting cells, not the IgM level in those cells. ► A mathematical model indicates deregulation of AP-1 and Bach2 by AhR is involved. ► Both pathways interfere with the bistable switch underlying B cell differentiation. ► Disruption of the bistable switch leads to all-or-none mode of suppression.

• OSTI ID: 22285255
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 268; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
CELL DIFFERENTIATION
DIOXIN
MICE
PLASMA CELLS
RECEPTORS
TRANSCRIPTION FACTORS