ArticleToxicological sciences : an official journal of the Society of Toxicology2010
A bistable switch underlying B-cell differentiation and its disruption by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 52 citations in OpenAlex.
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- Using the Key Characteristics Framework to Unlock the Mysteries of Aryl Hydrocarbon Receptor-Mediated Effects on the Immune System.Annual review of immunology · 2025Review
- Unique challenges and best practices for single cell transcriptomic analysis in toxicology.Current opinion in toxicology · 2024Article
- A multiscale spatial modeling framework for the germinal center response.Frontiers in immunology · 2024Article
- A New Bistable Switch Model of Alzheimer's Disease Pathogenesis.International journal of molecular sciences · 2022Article
- The transcriptional regulator HDP1 controls expansion of the inner membrane complex during early sexual differentiation of malaria parasites.Nature microbiology · 2022Article
- From Genes to Transcripts, a Tightly Regulated Journey inFrontiers in cellular and infection microbiology · 2020Review
- A multistationary loop model of ALS unveils critical molecular interactions involving mitochondria and glucose metabolism.PloS one · 2020Article
- Dynamical systems approaches to personalized medicine.Current opinion in biotechnology · 2019Review
- From Discrete to Continuous Modeling of Lymphocyte Development and Plasticity in Chronic Diseases.Frontiers in immunology · 2019Review
- Bridging the Data Gap FromFrontiers in public health · 2018Review
- Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites.Nature · 2017Article
- The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells.Toxicological sciences : an official journal of the Society of Toxicology · 2016Article
- A Network Model to Describe the Terminal Differentiation of B Cells.PLoS computational biology · 2016Article
- Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation.Drug metabolism and disposition: the biological fate of chemicals · 2015Review
- Inhibition of cathepsin B activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin.Environmental science and pollution research international · 2015Article
- Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.Environmental health perspectives · 2014Review
- Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion.BMC pharmacology & toxicology · 2014Article
- Ultrasensitive response motifs: basic amplifiers in molecular signalling networks.Open biology · 2013Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.