A bistable switch underlying B-cell differentiation and its disruption by the environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin

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

Research output: Research - peer-reviewArticle

  • 23 Citations

Abstract

The differentiation of B cells into antibody-secreting plasma cells upon antigen stimulation, a crucial step in the humoral immune response, is disrupted by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Several key regulatory proteins in the B-cell transcriptional network have been identified, with two coupled mutually repressive feedback loops among the three transcription factors B-cell lymphoma 6 (Bcl-6), B lymphocyte-induced maturation protein 1(Blimp-1), and paired box 5 (Pax5) forming the core of the network. However, the precise mechanisms underlying B-cell differentiation and its disruption by TCDD are not fully understood. Here we show with a computational systems biology model that coupling of the two feedback loops at the Blimp-1 node, through parallel inhibition of Blimp-1 gene activation by Bcl-6 and repression of Blimp-1 gene deactivation by Pax5, can generate a bistable switch capable of directing B cells to differentiate into plasma cells. We also use bifurcation analysis to propose that TCDD may suppress the B-cell to plasma cell differentiation process by raising the threshold dose of antigens such as lipopolysaccharide required to trigger the bistable switch. Our model further predicts that high doses of TCDD may render the switch reversible, thus causing plasma cells to lose immune function and dedifferentiate to a B cell-like state. The immunotoxic implications of these predictions are twofold. First, TCDD and related compounds would disrupt the initiation of the humoral immune response by reducing the proportion of B cells that respond to antigen and differentiate into antibody-secreting plasma cells. Second, TCDD may also disrupt the maintenance of the immune response by depleting the pool of available plasma cells through dedifferentiation.

LanguageEnglish (US)
Pages51-65
Number of pages15
JournalToxicological Sciences
Volume115
Issue number1
DOIs
StatePublished - May 2010

Profile

Cells
Switches
Impurities
1,4-dioxin
Cell Differentiation
B-Lymphocytes
Polychlorinated Dibenzodioxins
Plasmas
Proteins
Plasma Cells
Lymphocytes
Antigens
Genes
Feedback
Antibodies
Antibody-Producing Cells
B-Cell Lymphoma
Humoral Immunity
Lipopolysaccharides
Transcription Factors

Keywords

  • Bistability
  • Cellular reprogramming
  • Coupled feedback loops
  • Dedifferentiation
  • Immunotoxicity
  • TCDD

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

A bistable switch underlying B-cell differentiation and its disruption by the environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin. / Bhattacharya, Sudin; Conolly, Rory B.; Kaminski, Norbert E.; Thomas, Russell S.; Andersen, Melvin E.; Zhang, Qiang.

In: Toxicological Sciences, Vol. 115, No. 1, 05.2010, p. 51-65.

Research output: Research - peer-reviewArticle

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abstract = "The differentiation of B cells into antibody-secreting plasma cells upon antigen stimulation, a crucial step in the humoral immune response, is disrupted by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Several key regulatory proteins in the B-cell transcriptional network have been identified, with two coupled mutually repressive feedback loops among the three transcription factors B-cell lymphoma 6 (Bcl-6), B lymphocyte-induced maturation protein 1(Blimp-1), and paired box 5 (Pax5) forming the core of the network. However, the precise mechanisms underlying B-cell differentiation and its disruption by TCDD are not fully understood. Here we show with a computational systems biology model that coupling of the two feedback loops at the Blimp-1 node, through parallel inhibition of Blimp-1 gene activation by Bcl-6 and repression of Blimp-1 gene deactivation by Pax5, can generate a bistable switch capable of directing B cells to differentiate into plasma cells. We also use bifurcation analysis to propose that TCDD may suppress the B-cell to plasma cell differentiation process by raising the threshold dose of antigens such as lipopolysaccharide required to trigger the bistable switch. Our model further predicts that high doses of TCDD may render the switch reversible, thus causing plasma cells to lose immune function and dedifferentiate to a B cell-like state. The immunotoxic implications of these predictions are twofold. First, TCDD and related compounds would disrupt the initiation of the humoral immune response by reducing the proportion of B cells that respond to antigen and differentiate into antibody-secreting plasma cells. Second, TCDD may also disrupt the maintenance of the immune response by depleting the pool of available plasma cells through dedifferentiation.",
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