Disruption of human plasma cell differentiation by an environmental polycyclic aromatic hydrocarbon: a mechanistic immunotoxicological study.
Disruption of human plasma cell differentiation by an environmental polycyclic aromatic hydrocarbon: a mechanistic immunotoxicological study.
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DOI：
10.1186/1476-069x-9-15
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发表时间：
2010-03-24
期刊：
影响因子：
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通讯作者：
Sherr DH
中科院分区：
文献类型：
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作者：
Allan LL;Sherr DH
AhR是一种配体激活的转录因子，介导由环境PAH和HAH诱导的免疫抑制。最近，AhR在参与自身免疫的T细胞（Th 17和Treg）的发育中的关键作用已被证明，支持AhR在存在和不存在环境配体的情况下在免疫调节中起关键作用的假设。尽管这些结果与T细胞系统，很少有人知道的作用，AhR在B细胞的发展。我们已经证明，B细胞活化与CD 40配体，刺激模型的适应性免疫，诱导AhR表达在原代人B细胞，这表明，激活可能会增加人类B细胞对AhR配体的敏感性和AhR可能在B细胞的发展中发挥作用。为了测试这些可能性，我们开发了一种体外系统，其中诱导表达高AhR水平的活化的人B细胞分化为浆细胞。因此，苯并[a]芘，一个原型的环境AhR配体，对浆细胞分化的影响可以进行研究，这种化学物质可以利用基本上作为药物探针牵连的AhR在浆细胞发育中的作用。观察到以前无法达到的B细胞分化为浆细胞的水平（高达45%转化）。苯并[a]芘显著抑制了这种分化。在由CD 40配体诱导的初始增殖期之后和分化期开始之前立即进行γ-辐照可阻断细胞生长，但不影响细胞活力或浆细胞分化。无论γ射线是否抑制细胞生长，B [a]P均抑制分化。1)在分化阶段本身，CD 40 L活化的人B细胞进行浆细胞分化不需要广泛的增殖，和2）环境PAH阻断表达AhR的B细胞的增殖和分化。这些结果揭示了一种新的机制，即环境中普遍存在的多环芳烃可能会对人类B细胞介导的免疫产生负面影响。
The 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. To 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. A 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. 1) 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.