多氯聯苯/多氯呋喃中毒致人類幫手型T細胞17之活化與血清中抗核抗體濃度之上升

Abstract

西元1979年，台灣中部超過2000位居民因誤食遭多氯聯苯 (polychlorinated biphenyls) 及其加熱後之產物多氯呋喃 (polychlorinated dibenzofurans) 汙染之米糠油而中毒。這些中毒者其後被認定為「油症」患者，包括1991位直接暴露者與70位於母親懷孕時發生暴露之間接暴露者，他們的健康問題持續受台灣政府衛生主管機關之關切與追蹤。曾直接暴露於前述鹵代芳香烴 (halogenated aromatic hydrocarbons) 之女性油症患者，其死於全身性紅斑性狼瘡 (systemic lupus erythematosus) 之機率意外地被發現約為台灣民眾背景值之20倍。鹵代芳香烴暴露已知可擾亂人類與動物之免疫系統，然此種暴露是否於自體免疫性疾病之致病機轉中扮演角色目前未知。 芳香族羥基碳氫化合物接受器 (aryl hydrocarbon receptor) 是一依賴配體 (ligand-dependent) 之轉錄因子，其最為人所熟知之角色即為多氯聯苯與戴奧辛 (dioxin) 毒性之中介者。目前已知芳香族羥基碳氫化合物接受器之表現相對地限定於人類與老鼠之CD4+幫手型T細胞17 (T helper 17 cell)，也已知於誘發實驗性自體免疫腦脊髓炎 (experimental autoimmune encephalomyelitis，一種人類多發性硬化症的老鼠模式) 時同時活化芳香族羥基碳氫化合物接受器，將導致實驗性自體免疫腦脊髓炎之病理表現變得更為嚴重；另目前亦發現幫手型T細胞17之不當調控於人類及老鼠之全身性紅斑性狼瘡之致病機轉中佔有相當重要之地位。芳香族羥基碳氫化合物接受器之配體因此很可能於人類紅斑性狼瘡逐漸產生之過程中，扮演共同因子 (co-factor) 之角色。 在本研究中，我們發現女性油症患者 (直接暴露者) 血清中幫手型T細胞17其中一識別細胞激素 (signature cytokine) 介白素-22 (interleukin-22) 之濃度大幅上升，另一幫手型T細胞17之識別細胞激素介白素-17A (interleukin-17A) 之濃度亦小幅上升；我們進一步發現女性油症患者 (直接暴露者) 血清中介白素-22之濃度與總毒性當量 (total toxic equivalents) 呈現正相關。我們亦發現女性油症患者 (直接暴露者) 有較高比例其血清呈現抗核抗體 (antinuclear antibody) 檢測陽性反應，且抗核抗體之陽性反應亦與血清中介白素-22之濃度呈現正相關。我們還需要更進一步之實驗才可更深入瞭解「人類芳香族羥基碳氫化合物接受器-幫手型T細胞17-自體免疫」此軸線 (AHR- TH17-autoimmunity axis) 之全貌。

Over 2000 people in central Taiwan tragically ingested cooking rice oil contaminated with polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) in 1979. A Yucheng (“oil-disease” in Chinese) registry was then set up and maintained by governmental health department including 1991 directly exposed subjects and 70 children exposed in utero. The female victims of Yucheng directly exposed to the halogenated aromatic hydrocarbons (HAHs) were found to have unexpectedly increased mortality due to systemic lupus erythematosus (SLE) by almost 20 folds. Exposure to HAHs has been known to disrupt the immune system of both human and animals, but whether it is implicated in the pathogenesis of human autoimmune diseases is currently unknown. Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of PCBs and dioxins. It has been demonstrated that AHR expression is relatively restricted to the T helper 17 (TH17) cell subset in the CD4+ T cells of both human and mouse and activating AHR during induction of experimental autoimmune encephalomyelitis, a mouse model for human multiple sclerosis, was found to cause more prominent pathology. In addition, inappropriate regulation of TH17 cells is known to play important roles in the pathogenesis of SLE in both human and mouse. AHR ligands could thus represent co-factors in the development of TH17-related human SLE. Here we report that the female victims of Yucheng (directly-exposed) have significantly elevated serum levels of one of the TH17 signature cytokines, interleukin-22 (IL-22), and mildly elevated serum levels of another TH17 signature cytokine, interleukin-17A (IL-17A). The serum levels of IL-22 were further shown to be positively correlated with the serum total toxic equivalents (TEQs) in the Yucheng victims (directly-exposed). We also demonstrated that the prevalence of antinuclear antibody (ANA) seropositivity was higher in the Yucheng victims (directly-exposed) and positively related to the serum levels of IL-22. More work is necessary for revealing the full picture of the human AHR- TH17-autoimmunity axis.