The overall goal of this 5 year research plan is two-fold: (a) to characterize the molecular mechanism for? impairment of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like? compounds; and (b) to develop a computational model describing the biochemical pathways that regulate B? cell differentiation and the interaction of this pathway with the aryl hydrocarbon reception (AhR). Previous? studies have established the B cell as a sensitive cellular target for TCDD as evidenced by suppression of? immunoglobulin (lg)M through a direct effect on B cells involving the AhR. Moreover, suppression of the IgM? response by TCDD is mediated at the level of transcription and, in part, occurs through AhR binding to dioxin? response elements (ORE) in regulatory domains within the Ig heavy chain (IgH) 3'a enhancer. Importantly,? in addition to IgH suppression, the Ig kappa light chain (Igk), IgM joining chain (J chain) and X-box protein-1? (XBP-1), which are essential for IgM assembly and secretion, are also markedly suppressed by TCDD? suggesting the involvement of additional targets other than just the IgH 3'a enhancer. Moreover, TCDD? alters the levels of B lymphocyte.-induced maturation protein-1 (Blimp-1), a master regulatory of B cell? differentiation and its downstream target, Pax5, a transcriptional represser of B cell differentiation, which? represses IgH, Igk, J chain and XBP-1. We also show that TCDD treatment of B cells: (a) altered the? magnitude of DNA methylation and MRNA levels of DNA methylating enzymes, Dnmt3b, which putatively? influences the expression of genes crucial to B cell differentiation, including Pax5; (b) is functionally? antagonized by IFNg; and (c) rapidly induces the suppressor of cytokine signaling-2 (SOCS-2), a protein? that negatively regulates signaling through cytokine receptors coupled to the JAK/STAT pathway, such as? the IFNg receptor (IFNgR). The project objective is to test the hypothesis: Suppression of the primary? humoral immune response by AhR agonists is mediated through changes in the B cell differentiation? program via a mechanism that is blocked by IFNg. A computational description of the biochemical pathway? of B cell differentiation and the direct interactions of AhR agonists on this pathway, will provide a mechanistic? approach for predicting the effects of AhR agonists, alone and in combination as complex mixtures, on the? pathway and on humoral immune responses.
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