title: Stochastic modeling of B lymphocyte terminal differentiation and its suppression by dioxin.
abstract: BACKGROUND
  Upon antigen encounter, naïve B lymphocytes differentiate into antibody-secreting plasma cells. This humoral immune response is suppressed by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds, which belong to the family of aryl hydrocarbon receptor (AhR) agonists.
  
  
  RESULTS
  To achieve a better understanding of the immunotoxicity of AhR agonists and their associated health risks, we have used computer simulations to study the behavior of the gene regulatory network underlying B cell terminal differentiation. The core of this network consists of two coupled double-negative feedback loops involving transcriptional repressors Bcl-6, Blimp-1, and Pax5. Bifurcation analysis indicates that the feedback network can constitute a bistable system with two mutually exclusive transcriptional profiles corresponding to naïve B cells and plasma cells. Although individual B cells switch to the plasma cell state in an all-or-none fashion when stimulated by the polyclonal activator lipopolysaccharide (LPS), stochastic fluctuations in gene expression make the switching event probabilistic, leading to heterogeneous differentiation response among individual B cells. Moreover, stochastic gene expression renders the dose-response behavior of a population of B cells substantially graded, a result that is consistent with experimental observations. The steepness of the dose response curve for the number of plasma cells formed vs. LPS dose, as evaluated by the apparent Hill coefficient, is found to be inversely correlated to the noise level in Blimp-1 gene expression. Simulations illustrate how, through AhR-mediated repression of the AP-1 protein, TCDD reduces the probability of LPS-stimulated B cell differentiation. Interestingly, stochastic simulations predict that TCDD may destabilize the plasma cell state, possibly leading to a reversal to the B cell phenotype.
  
  
  CONCLUSIONS
  Our results suggest that stochasticity in gene expression, which renders a graded response at the cell population level, may have been exploited by the immune system to launch humoral immune response of a magnitude appropriately tuned to the antigen dose. In addition to suppressing the initiation of the humoral immune response, dioxin-like compounds may also disrupt the maintenance of the acquired immunity.
authors.affiliation: Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA. qzhang@thehamner.org
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sudin
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Kline
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D002454:Cell Differentiation; D004147:Dioxins / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists; D013269:Stochastic Processes; D049490:Systems Biology
chemical_list: D004147:Dioxins; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon