The long winding road toward understanding the molecular mechanisms for B-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review.

FIG. 1.

Schematic of the human versus mouse IgH gene locus. Simplified diagram of a rearranged human and mouse Ig heavy chain (IgH) locus which includes the variable heavy chain promoter (V_H), the intronic or μ enhancer (Eμ), the heavy chain constant regions for the μ-, δ-, γ-, ϵ-, α-isotypes and subclasses (black rectangles), the germline promoters upstream of each heavy chain constant region (open rectangles), and the enhancers (hs3, hs1,2, and hs4) of the 3′IgH regulatory region (3′IgHRR).

FIG. 2.

Schematic representation of the regulators controlling B cell to plasma cell differentiation. Positive regulation is depicted with arrows and negative regulation is depicted by brackets.