Disruption of human plasma cell differentiation by an environmental polycyclic aromatic hydrocarbon: a mechanistic immunotoxicological study

Lenka L Allan,David H Sherr

doi:10.1186/1476-069x-9-15

Lenka L Allan, David H Sherr

Open Access

https://doi.org/10.1186/1476-069x-9-15

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Abstract

BackgroundThe AhR is a ligand-activated transcription factor that mediates immunosuppression induced by environmental PAH and HAH. Recently, a critical role for the AhR in development of T cells involved in autoimmunity (Th17 and Treg) has been demonstrated, supporting the hypothesis that the AhR plays a key role in immune regulation both in the presence and absence of environmental ligands. Despite these results with T cells systems, little is known of the role that the AhR plays in B cell development. We have demonstrated that B cell activation with CD40 ligand, a stimulus that models adaptive immunity, induces AhR expression in primary human B cells, suggesting that activation may increase human B cell sensitivity to AhR ligands and that the AhR may play a role in B cell development.MethodsTo test these possibilities, we developed an in vitro system in which activated human B cells expressing high AhR levels are induced to differentiate into plasma cells. Consequently, the effects of benzo [a]pyrene, a prototypic environmental AhR ligand, on plasma cell differentiation could be investigated and this chemical could be exploited essentially as drug probe to implicate the role of the AhR in plasma cell development.ResultsA previously unattainable level of B cell differentiation into plasma cells (up to 45% conversion) was observed. Benzo [a]pyrene significantly suppressed that differentiation. γ-Irradiation after an initial proliferation phase induced by CD40 ligand and immediately prior to initiation of the differentiation phase blocked cell growth but did not affect cell viability or plasma cell differentiation. B [a]P suppressed differentiation whether or not cell growth was inhibited by γ-irradiation.Conclusions1) Extensive proliferation is not required during the differentiation phase per se for CD40L-activated human B cells to undergo plasma cell differentiation, and 2) an environmental PAH blocks both proliferation and differentiation of AhR expressing B cells. The results uncover a new mechanism by which environmentally ubiquitous PAHs may negatively impact human B cell-mediated immunity.

Highlights

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates immunosuppression induced by environmental Polycyclic Aromatic Hydrocarbon(s) (PAH) and Halogenated Aromatic Hydrocarbon(s) (HAH)
To begin to bridge this gap, we developed an in vitro model to demonstrate that activation of primary human B cells with CpG or CD40L, stimuli that mimic innate or adaptive B cell responses respectively, dramatically increases AhR expression [29]
Generation of plasma cells using two-step cell cultures In order to address whether environmental AhR ligands affect the differentiation of human B cells into plasma cells, it was necessary first to develop an in vitro differentiation system in which significant numbers of human plasma cells could be reliably generated from activated, AhRhigh B cells

Summary

Introduction

The AhR is a ligand-activated transcription factor that mediates immunosuppression induced by environmental PAH and HAH. A critical role for the AhR in development of T cells involved in autoimmunity (Th17 and Treg) has been demonstrated, supporting the hypothesis that the AhR plays a key role in immune regulation both in the presence and absence of environmental ligands. Despite these results with T cells systems, little is known of the role that the AhR plays in B cell development. Carcinogenic PAHs, such as benzo [a]pyrene (B [a]P), suppress both humoral (B cell-mediated) and cellular (T cell-mediated) immune responses Most of these adverse effects are mediated by the aryl hydrocarbon receptor (AhR), a cytosolic receptor/transcription factor [1]. Halogenated hydrocarbons impair the ability of thymic stroma to support developing T cell growth and/or differentiation [4,5,6,7,8,9,10,11,12]

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