Inhibition of Calcium-Dependent B Cell Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has previously been shown to directly suppress humoral immunity in mice when administered either in vivo or to isolated low-density B lymphocytes in culture. Because TCDD-mediated suppression of the antibody forming cell response to both LPS and SRBC was found to require early xenobiotic exposure (i.e., within 3 and 24 hr of antigen addition, respectively), an early B cell activation event is most likely to be affected by TCDD. Antigen recognition via the surface immunoglobulin (sIg) receptor leads to B cell activation and clonal expansion, priming the cell to secrete specific antibody. The signal transduction events triggered by either antigen or anti-Ig antibodies are similar and relatively well characterized in comparison to other models of B cell activation, such as stimulation by LPS or activated T-helper cell membranes. In order to study the potential effects of TCDD on early B cell activation events, we examined murine low-density B cell responses to activation by anti-IgM in the presence of immunosuppressive concentrations of TCDD. Compared to vehicle controls, TCDD inhibited anti-IgM-stimulated proliferative responses but not Ia expression induced by sIgM ligation. In addition, B cell proliferative responses to the combination of PMA and ionomycin were suppressed by up to 50% of control levels at 30 nM TCDD, indicating that TCDD may disrupt signaling pathways distal to phospholipase C. The magnitude of TCDD-induced suppression of the PMA plus ionomycin induced proliferative response was dependent upon the ionomycin concentration but not the PMA concentration, suggesting that TCDD manifests its antiproliferative effects on B cells by inhibiting calcium-dependent activation.