title: A bistable switch underlying B-cell differentiation and its disruption by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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.
authors.affiliation: Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA. sbhattacharya@thehamner.org
authors.forename: Sudin
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D054337:Cell Dedifferentiation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005812:Genes, Switch / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D000072317:Polychlorinated Dibenzodioxins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1