2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells

Abstract

Suppression of the primary antibody response is particularly sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice; however, surprisingly little is known concerning the effects of TCDD on humoral immunity or B cell function in humans. Results from a limited number of previous studies, primarily employing in vitro activation models, suggested that human B cell effector function is suppressed by TCDD. The present study sought to extend these findings by investigating, in primary human B cells, the effects of TCDD on several critical stages leading to antibody secretion including activation and plasmacytic differentiation using an in vitro CD40 ligand activation model. These studies revealed important differences in the response of human and mouse B cells to TCDD, the most striking being altered expression of plasmacytic differentiation regulators, B lymphocyte-induced maturation protein 1 and paired box protein 5, in mouse but not human B cells. The activation of human B cells was profoundly impaired by TCDD, as evidenced by decreased expression of activation markers CD80, CD86, and CD69. The impaired activation correlated with decreased cell viability, which prevented the progression of human B cells toward plasmacytic differentiation. TCDD treatment also attenuated the early activation of mitogen-activated protein kinases (MAPK) and Akt signaling in human B cells. Collectively, the present study provided experimental evidence for novel mechanisms by which TCDD impairs the effector function of primary human B cells.

The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells

“…1A and B). The results are in accordance with a previous report showing that TCDD significantly suppresses the number of cells secreting IgM (Lu et al, 2011). The IC 50 from the two endpoints were found to differ over 150-fold.…”

“…Within the immune system, TCDD has been established to directly alter B-cell function as evidenced by the suppression of humoral immune responses (Crawford et al, 2003;Sulentic et al, 1998). Although much of the current understanding of TCDD-induced B-cell dysfunction has been derived from mouse studies and murine cell lines, recent publications using primary cells have confirmed that TCDD suppresses the activation and differentiation of human B cells (Lu et al, 2010(Lu et al, , 2011Phadnis-Moghe et al, 2015). Furthermore, results from studies using a primary B-cell model indicated that a subset of the human donors did not respond to TCDD suggesting that this model might be valuable in modeling interindividual variability (Lu et al, 2010).…”

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

“…TCDD is a ubiquitous environment contaminant, which exhibits a wide spectrum of toxicity including immunotoxicity (51, 52). TCDD has been shown to suppress humoral immunity by disrupting the function of human mature B cells (31, 53, 54). Here the reported impairment of B cell development may represent an additional mechanism of immune suppression by TCDD.…”

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

“…In addition, our data indicated that ITE inhibited B cell differentiation into Ig-producing plasma cells. In previous papers, the highly potent AhR agonist TCDD was shown to suppress the production of IgM in human B cells and a lipopolysaccharide (LPS)-induced transformed mouse B cell line, CH12.LX, and to inhibit the differentiation into Igproducing plasma cells (11,12,20,21). More recently, it was reported that benzo[a]pyrene also suppressed the differentiation into plasma cells in human B cells (2).…”