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A Transcriptional Regulatory Switch Underlying B-Cell Terminal Differentiation and Its Disruption by Dioxin (S)
Citation:
Bhattacharya, S., R. CONOLLY, M. E. Andersen, AND Q. Zhang. A Transcriptional Regulatory Switch Underlying B-Cell Terminal Differentiation and Its Disruption by Dioxin (S). Presented at International Conference on Systems Biology, Gothenburg, SWEDEN, August 23 - 27, 2008.
Impact/Purpose:
The terminal differentiation of B cells in lymphoid organs into antibody-secreting plasma cells upon antigen stimulation is a crucial step in the humoral immune response. The architecture of the B-cell transcriptional regulatory network consists of coupled mutually-repressive feedback loops involving the three transcription factors Bcl6, Blimp1 and Pax5. This structure forms the basis of an irreversible bistable switch directing the B-cell to plasma cell differentiation process – i.e., the switch remains on even after the activating stimulus (antigen) is removed. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress the humoral immune response by interfering with this differentiation program. We have developed a computational model of the biochemical pathways that regulate B-cell differentiation, and the molecular mechanism by which TCDD impairs this process through the action of the aryl hydrocarbon receptor (AhR). Using a kinetic model and bifurcation analysis, we propose that TCDD regulates the proportion of B-cells that differentiate into plasma cells by raising the threshold dose of antigen lipopolysaccharide (LPS) required to trigger the differentiation switch. We also show that stochastic modeling of gene expression, which allows cell-to-cell differences in content of signaling proteins, introduces distributional characteristics to the timing and probability of differentiation among a population of B-cells. This cell-to-cell variability is likely to be a key determinant of dose-response and sensitivity of individual cells to differentiation.
Description:
The terminal differentiation of B cells in lymphoid organs into antibody-secreting plasma cells upon antigen stimulation is a crucial step in the humoral immune response. The architecture of the B-cell transcriptional regulatory network consists of coupled mutually-repressive feedback loops involving the three transcription factors Bcl6, Blimp1 and Pax5. This structure forms the basis of an irreversible bistable switch directing the B-cell to plasma cell differentiation process – i.e., the switch remains on even after the activating stimulus (antigen) is removed. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress the humoral immune response by interfering with this differentiation program. We have developed a computational model of the biochemical pathways that regulate B-cell differentiation, and the molecular mechanism by which TCDD impairs this process through the action of the aryl hydrocarbon receptor (AhR). Using a kinetic model and bifurcation analysis, we propose that TCDD regulates the proportion of B-cells that differentiate into plasma cells by raising the threshold dose of antigen lipopolysaccharide (LPS) required to trigger the differentiation switch. We also show that stochastic modeling of gene expression, which allows cell-to-cell differences in content of signaling proteins, introduces distributional characteristics to the timing and probability of differentiation among a population of B-cells. This cell-to-cell variability is likely to be a key determinant of dose-response and sensitivity of individual cells to differentiation.
URLs/Downloads:
A Transcriptional Regulatory Switch Underlying B-Cell Terminal Differentiation and Its Disruption by Dioxin (S) (PDF, NA pp, 8 KB, about PDF)A Transcriptional Regulatory Switch Underlying B-Cell Terminal Differentiation and Its Disruption by Dioxin (poster) (PDF, NA pp, 185 KB, about PDF)