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.Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; B cell; humoral immunity; immune suppression; AhR.Halogenated aromatic hydrocarbons such as the polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls are persistent environmental toxicants. The most potent of this class of chemicals is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is produced as a by-product during a variety of industrial and municipal processes, many of which involve the combustion of organic materials in the presence of chlorine. TCDD has generated much public concern due to several highly publicized incidents of human and wildlife exposure (reviewed by White and Birnbaum, 2009). Additionally, the sensitivity of rodent models to TCDD-induced toxicity has fueled concern regarding the potential health risks to humans. TCDD produces a broad range of biological effects in animal and cellular models including death, a generalized wasting syndrome, lymphoid involution (especially of the thymus), hepatotoxicity, cardiotoxicity, teratogenicity, developmental toxicity, carcinogenesis, neurotoxicity, immunotoxicity, and various biochemical effects (reviewed by Birnbaum and Tuomisto, 2000).Alterations in immune function, primarily immune suppression, have been observed in virtually every species studied and occurs at doses that do not produce obvious signs of toxicity in vivo and at noncytotoxic concentrations in vitro (Holsapple et al., 1991b;Kerkvliet, 2002). These alterations include ...

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

“…These results, together with the significant decreases in IgG and IgM titers, indicated that the immune responses were suppressed. These results were consistent with previous reports following human accident exposures (Sulentic and Kaminski, 2011b), indicating that the selected murine model accurately recapitulated a paradigm of the chronic human exposure of TCDD and could provide information for further studies. One of the reasons leading to dramatically reduced IgG and IgM production could be the decrease in number of the antibody-producing plasma cells, due to the arrest in the B cell maturation.…”

“…Moreover, NR4a1 is a critical transcriptional regulator of Foxp3 that itself is a master regulator of the development and function of Treg cells (Ellmeier and Taniuchi, 2014). While there is a consensus that TCDD exposure is a risk factor for certain cancers including NHL (Sulentic and Kaminski, 2011a), the carcinogenic potential of TCDD had been a subject of controversy (Baccarelli et al, 2004). Indeed, TCDD has both anti-inflammatory and cancer-promoting activities, and there are many factors, often counter-acting, involved in the physiology of the long term AhR activation as a result of chronic TCDD exposure, thus the adverse effects on human health can be indirect and delayed.…”

“…The role of AhR in the Th17 and T regulatory (Treg) cell development is firmly established (Ho and Steinman, 2008). B cells are also highly sensitive targets of TCDD (Sulentic and Kaminski, 2011b). Epidemiologic evidence shows that TCDD exposure depresses humoral immunity in human subjects.…”

“…Epidemiologic evidence shows that TCDD exposure depresses humoral immunity in human subjects. As such, both Seveso accident subjects with the highest TCDD exposure and Vietnam Veterans exhibited decreased plasma IgG levels and increased incidence of lymphatic tumors, especially non-Hodgkin's lymphoma (NHL) (Sulentic and Kaminski, 2011b).…”

Impact of environmental factors on alloimmunity and transplant fate

“…Tolerance induction was associated with expansion of CD4 + C-D25 + Foxp3 + Tregs. While TCDD has been shown to inhibit B cell differentiation and antibody production in vitro (91)(92)(93)(94), no studies have yet demonstrated a potential benefit in transplantation. In humans, there is some observational evidence that traffic air pollution may shorten the life of lung transplants through the development of bronchiolitis obliterans syndrome (95).…”