Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells

Abstract

Previous studies have demonstrated that most of the intraspecies variation in sensitivity to the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including suppression of antibody responses, in murine models is due to single nucleotide polymorphisms (SNPs) within the aryl hydrocarbon receptor (AhR) gene. The underlying reason for variation in sensitivity to TCDD-induced suppression of IgM responses among humans is not well understood, but is thought, in part, to be a result of different polymorphic forms of the AhR expressed by different individuals. In this study, the functional properties of six (P517S, R554K, V570I, V570I+P517S, R554K+V570I and P517S+R554K+V570I) human AhR variants were examined in the human B cell line, SKW 6.4. TCDD-induced Cyp1B1 and Cyp1A2 mRNA expression levels and Cyp1B1-regulated reporter gene activity, used for comparative purposes, were markedly lower in SKW cells containing the R554K SNP than in SKW-AHR+ (control AhR) cells. Furthermore, all AhR variants were able to mediate TCDD-induced suppression of the IgM response; however, a combined P517S+R554K+V570I variant partially reduced sensitivity to TCDD-mediated suppression of IgM secretion. Collectively, our findings show that the R554K human AhR SNP alone altered sensitivity of human B cells to TCDD-mediated induction of Cyp1B1 and Cyp1A2. By contrast, attenuation of TCDD-induced IgM suppression required a combination of all three SNPs P517S, R554K, and V570I.

Suppression of the IgM Response by Aryl Hydrocarbon Receptor Activation in Human Primary B Cells Involves Impairment of Immunoglobulin Secretory Processes

“…A second interesting phenomenon that we and others have described in B cells is that AHR activation must occur within the first 24 h post B cell activation to induce suppression of the IgM response (Kovalova et al, 2016a). The temporal relationship between AHR activation and the activation of the B cell suggests Figure 4.…”

“…Murine studies have shown that suppression of the IgM response by AHR ligands is closely linked to a decrease in mRNA levels for the immunoglobulin chains (IgH, IgJ, and Igj chains) (Schneider et al, 2008). Previous studies have also demonstrated that AHR activation impairs IgM responses by human B cells to a variety of stimuli including: PWM; co-stimulation by CD40L with cytokines; and toxic shock syndrome toxin superantigen (Kovalova et al, 2016a;Lu et al, 2011;Phadnis-Moghe et al, 2015;Wood and Holsapple, 1993). It has been broadly assumed that the molecular mechanisms responsible for immune suppression by AHR ligands, including suppression of the IgM antibody response, would be similar across animal species.…”

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

“…Metabolites 2019, 9, exposure, the host would have a dampened inflammatory response, due to the immature B cells. It was also noted that the major window for TCDD and AHR to affect B cells is 12 h after stimulation [29,32]. This is important because if there a sub-chronic exposure of TCDD, the B cells would be affected throughout the exposure, and when the exposure stopped there is a possibility of a buildup of LPS that was not cleared by the delayed B cells.…”

Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

“…Studies in mouse, rat and human B lymphocytes show similar levels both in terms of the magnitude of TCDD-induced IgM suppression as well as similarity in time-of–addition kinetics (Kovalova et al, 2016). Concordance across all three animal species suggested a common mode of action.…”

“…Additionally, the window of sensitivity during which TCDD can suppress IgM secretion is similar between mouse, human and rat B cells, suggesting a common mechanism of action of IgM suppression. Specifically, TCDD must be added to the activated B cells within the initial 12 h post-stimulation to suppress IgM secretion (Dooley and Holsapple, 1988; Sulentic et al ., 1998; Kovalova et al ., 2016). The relatively narrow window of sensitivity suggests TCDD-mediated interference with a critical event shortly following B-cell activation.…”