Institute for Environmental Medical Research, Molecular Immunology Unit, 40225 Düsseldorf, Germany.
Toxicol Sci. 2010 Nov;118(1):98-107. doi: 10.1093/toxsci/kfq232. Epub 2010 Aug 20.
The toxic environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunomodulatory chemical. TCDD activates the aryl hydrocarbon receptor (AhR) and suppresses peripheral humoral and cellular adaptive immune responses. Though the major route of uptake is via food, little is known until now on the immunotoxic effects of TCDD on the gut-associated lymphoid tissue. We show here that AhR is strongly expressed along the small intestine, especially in intestinal epithelial cells (IEC). The AhR marker gene cyp1a1 is induced in IEC by oral TCDD exposure. We asked how TCDD affects oral tolerance, a unique function of mucosal immunity. C57BL/6 mice were injected with 10 μg/kg body weight TCDD and fed with ovalbumin (OVA) in a high-dose tolerization protocol. Mice were immunized and boosted with OVA on days 12, 23, and 55 after tolerization. Five of 14, 6 of 15, and 13 of 14 TCDD-treated mice generated OVA-specific immunoglobulin (Ig)G1 antibodies after the first, second, and third immunization with OVA, respectively. Only one mouse harbored anti-OVA IgG1 antibodies in the control group even after the third immunization with OVA. OVA-specific IgA in fecal samples of tolerized and TCDD-exposed mice could be detected at the levels of nontolerized mice, whereas completely absent in tolerant control mice. Correlated to this, we found in TCDD-treated mice an increase in interleukin-6 producing CD103+ dendritic cells (DC) present in the gut-draining mesenteric lymph nodes (MLN) and a small increase in the frequency of Th17 cells. Neither the frequencies nor the absolute numbers of immune cells in the lamina propria (LP) or in intraepithelial lymphocytes were changed by TCDD treatment. Our data not only have implications for food allergies in settings of environmental exposure but also raise concerns regarding the harmlessness of overdosing potential AhR agonist in food, which needs to be studied further.
有毒的环境污染物 2,3,7,8-四氯二苯并对二恶英（TCDD）是一种有效的免疫调节化学物质。TCDD 激活芳香烃受体（AhR）并抑制外周体液和细胞适应性免疫反应。尽管主要的摄取途径是通过食物，但到目前为止，人们对 TCDD 对肠道相关淋巴组织的免疫毒性知之甚少。我们在这里表明，AhR 在小肠中强烈表达，特别是在肠上皮细胞（IEC）中。AhR 标记基因 cyp1a1 被口服 TCDD 暴露诱导在 IEC 中表达。我们想知道 TCDD 如何影响口服耐受，这是黏膜免疫的一种独特功能。C57BL/6 小鼠用 10μg/kg 体重 TCDD 注射，并在高剂量致敏方案中用卵清蛋白（OVA）喂养。在致敏后第 12、23 和 55 天，用 OVA 对小鼠进行免疫接种和加强免疫。在接受第一次、第二次和第三次 OVA 免疫接种后，分别有 14 只、15 只和 14 只 TCDD 处理的小鼠产生 OVA 特异性 IgG1 抗体。在对照组中，即使在第三次用 OVA 免疫接种后，也只有一只小鼠产生抗 OVA IgG1 抗体。在致敏和 TCDD 暴露的小鼠的粪便样本中可以检测到与未致敏小鼠相当的 OVA 特异性 IgA，而在致敏对照组小鼠中则完全不存在。与此相关的是，我们发现在 TCDD 处理的小鼠中，存在于肠道引流肠系膜淋巴结（MLN）中的产生白细胞介素-6 的 CD103+树突状细胞（DC）增加，并且 Th17 细胞的频率略有增加。TCDD 处理并未改变固有层（LP）或上皮内淋巴细胞中的免疫细胞的频率或绝对数量。我们的数据不仅对环境暴露背景下的食物过敏有影响，而且还对食物中潜在的 AhR 激动剂过量的无害性提出了担忧，这需要进一步研究。
