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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 郭育良 | |
dc.contributor.author | Nian-Wei Lee | en |
dc.contributor.author | 李念偉 | zh_TW |
dc.date.accessioned | 2021-06-16T17:26:47Z | - |
dc.date.available | 2017-09-17 | |
dc.date.copyright | 2012-09-17 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-16 | |
dc.identifier.citation | 1 Zheng, G. J., Leung, A. O., Jiao, L. P. & Wong, M. H. Polychlorinated dibenzo-p-dioxins and dibenzofurans pollution in China: sources, environmental levels and potential human health impacts. Environment international 34, 1050-1061, doi:10.1016/j.envint.2008.02.011 (2008).
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Immunological reviews 223, 87-113, doi:10.1111/j.1600-065X.2008.00628.x (2008). 12 Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106-109, doi:10.1038/nature06881 (2008). 13 Dong, G. et al. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chinese medical journal 116, 543-548 (2003). 14 Wong, C. K. et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 127, 385-393, doi:10.1016/j.clim.2008.01.019 (2008). 15 Kang, H. K., Liu, M. & Datta, S. K. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol 178, 7849-7858 (2007). 16 Wang, D. et al. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. International immunology 17, 1179-1191, doi:10.1093/intimm/dxh295 (2005). 17 Hsu, S. T. et al. Discovery and epidemiology of PCB poisoning in Taiwan: a four-year followup. Environmental health perspectives 59, 5-10 (1985). 18 Tsai, P. C., Ko, Y. C., Huang, W., Liu, H. S. & Guo, Y. L. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. The Science of the total environment 374, 216-222, doi:10.1016/j.scitotenv.2006.12.024 (2007). 19 Yu, M. L., Guo, Y. L., Hsu, C. C. & Rogan, W. J. Increased mortality from chronic liver disease and cirrhosis 13 years after the Taiwan 'yucheng' ('oil disease') incident. American journal of industrial medicine 31, 172-175 (1997). 20 Guo, Y. L., Yu, M. L., Hsu, C. C. & Rogan, W. J. Chloracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-year follow-Up of the Taiwan Yucheng cohort. Environmental health perspectives 107, 715-719 (1999). 21 Costenbader, K. H., Feskanich, D., Stampfer, M. J. & Karlson, E. W. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis and rheumatism 56, 1251-1262, doi:10.1002/art.22510 (2007). 22 D'Cruz, D. P., Khamashta, M. A. & Hughes, G. R. Systemic lupus erythematosus. Lancet 369, 587-596, doi:10.1016/S0140-6736(07)60279-7 (2007). 23 Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. The New England journal of medicine 349, 1526-1533, doi:10.1056/NEJMoa021933 (2003). 24 Shmerling, R. H. Autoantibodies in systemic lupus erythematosus--there before you know it. The New England journal of medicine 349, 1499-1500, doi:10.1056/NEJMp038142 (2003). 25 Stockinger, B., Hirota, K., Duarte, J. & Veldhoen, M. External influences on the immune system via activation of the aryl hydrocarbon receptor. Seminars in immunology 23, 99-105, doi:10.1016/j.smim.2011.01.008 (2011). 26 Brembilla, N. C. et al. In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. PloS one 6, e18741, doi:10.1371/journal.pone.0018741 (2011). 27 Pan, H. F., Ye, D. Q. & Li, X. P. Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus. Nature clinical practice. Rheumatology 4, 352-353, doi:10.1038/ncprheum0815 (2008). 28 Schmidt-Weber, C. B., Akdis, M. & Akdis, C. A. TH17 cells in the big picture of immunology. The Journal of allergy and clinical immunology 120, 247-254, doi:10.1016/j.jaci.2007.06.039 (2007). 29 Phan, T. G., Wong, R. C. & Adelstein, S. Autoantibodies to extractable nuclear antigens: making detection and interpretation more meaningful. Clinical and diagnostic laboratory immunology 9, 1-7 (2002). 30 Smeenk, R. et al. Antibodies to DNA in patients with systemic lupus erythematosus. Their role in the diagnosis, the follow-up and the pathogenesis of the disease. Clinical rheumatology 9, 100-110 (1990). 31 Munves, E. F. & Schur, P. H. Antibodies to Sm and RNP. Prognosticators of disease involvement. Arthritis and rheumatism 26, 848-853 (1983). 32 Wolk, K., Witte, E., Witte, K., Warszawska, K. & Sabat, R. Biology of interleukin-22. Seminars in immunopathology 32, 17-31, doi:10.1007/s00281-009-0188-x (2010). 33 Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241-254, doi:10.1016/j.immuni.2004.07.007 (2004). 34 Wolk, K. et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. European journal of immunology 36, 1309-1323, doi:10.1002/eji.200535503 (2006). 35 Saurat, J. H. & Sorg, O. Chloracne, a misnomer and its implications. Dermatology 221, 23-26, doi:10.1159/000290672 (2010). 36 Kerkvliet, N. I. Recent advances in understanding the mechanisms of TCDD immunotoxicity. International immunopharmacology 2, 277-291 (2002). 37 Block, S. R., Winfield, J. B., Lockshin, M. D., D'Angelo, W. A. & Christian, C. L. Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. The American journal of medicine 59, 533-552 (1975). 38 Deapen, D. et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis and rheumatism 35, 311-318 (1992). 39 Esteller, M. Epigenetics in cancer. The New England journal of medicine 358, 1148-1159, doi:10.1056/NEJMra072067 (2008). 40 Mann, M. R. et al. Selective loss of imprinting in the placenta following preimplantation development in culture. Development 131, 3727-3735, doi:10.1242/dev.01241 (2004). 41 Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the United States of America 105, 17046-17049, doi:10.1073/pnas.0806560105 (2008). 42 Morel, L. Genetics of SLE: evidence from mouse models. Nature reviews. Rheumatology 6, 348-357, doi:10.1038/nrrheum.2010.63 (2010). 43 Nguyen, L. P. & Bradfield, C. A. The search for endogenous activators of the aryl hydrocarbon receptor. Chemical research in toxicology 21, 102-116, doi:10.1021/tx7001965 (2008). 44 Van den Berg, M. et al. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental health perspectives 106, 775-792 (1998). 45 Steenland, K. & Deddens, J. Dioxin: exposure-response analyses and risk assessment. Industrial health 41, 175-180 (2003). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64020 | - |
dc.description.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。 | zh_TW |
dc.description.abstract | 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. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:26:47Z (GMT). No. of bitstreams: 1 ntu-101-R98841023-1.pdf: 3463894 bytes, checksum: 3131f4abe316ff6f6b297758e6fb1568 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 圖目錄....2
表目錄....6 Introduction....7 Materials and methods....10 Results....13 The Yucheng victims had significantly elevated serum levels of IL-22 but mildly elevated IL-17A....13 The serum levels of IFN-γ and IL-4 in the Yucheng victims were indistinguishable from those in the control subjects....13 The serum levels of IL-22 were positively correlated with the serum total TEQs in the Yucheng victims....14 The prevalence of ANA seropositivity was higher in the Yucheng victims and positively related to the serum levels of IL-22....15 Discussion ....16 References ....20 Figures....28 Tables....54 圖目錄 Figure 1 Ligand-activated signal transduction of the AHR....28 Figure 2 Functional subsets of CD4 T cells....29 Figure 3 The serum levels of IL-17A and IL-22 in the control subjects and Yucheng victims....31 Figure 3 (Continued) The serum levels of IFN-γ and IL-4 in the control subjects and Yucheng victims....32 Figure 4-1 The relation between the predicted serum total TEQ in 1979 and serum level of IL-17A or IL-22 in the Yucheng victims....33 Figure 4-1 (Continued) The relation between the predicted serum total TEQ in 1979 and serum level of IFN-γ or IL-4 in the Yucheng victims....34 Figure 4-2 The relation between the logarithm (base 10) of the predicted serum total TEQ in 1979 and logarithm (base 10) of the serum level of IL-17A or IL-22 in the Yucheng victims....35 Figure 4-2 (Continued) The relation between the logarithm (base 10) of the predicted serum total TEQ in 1979 and logarithm (base 10) of the serum level of IFN-γ or IL-4 in the Yucheng victims....36 Figure 5-1 The relation between the predicted serum total TEQ in 1986 and the serum level of IL-17A or IL-22 in the Yucheng victims....37 Figure 5-1 (Continued) The relation between the predicted serum total TEQ in 1986 and the serum level of IFN-γ or IL-4 in the Yucheng victims....38 Figure 5-2 The relation between the logarithm (base 10) of the predicted serum total TEQ in 1986 and logarithm (base 10) of the serum level of IL-17A or IL-22 in the Yucheng victims....39 Figure 5-2 (Continued) The relation between the logarithm (base 10) of the predicted serum total TEQ in 1986 and logarithm (base 10) of the serum level of IFN-γ or IL-4 in the Yucheng victims....40 Figure 6-1 The relation between the predicted serum total TEQ in 1993 and the serum level of IL-17A or IL-22 in the Yucheng victims....41 Figure 6-1 (Continued) The relation between the predicted serum total TEQ in 1993 and the serum level of IFN-γ or IL-4 in the Yucheng victims....42 Figure 6-2 The relation between the logarithm (base 10) of the predicted serum total TEQ in 1993 and logarithm (base 10) of the serum level of IL-17A or IL-22 in the Yucheng victims....43 Figure 6-2 (Continued) The relation between the logarithm (base 10) of the predicted serum total TEQ in 1993 and logarithm (base 10) of the serum level of IFN-γ or IL-4 in the Yucheng victims....44 Figure 7-1 The relation between the predicted serum total TEQ in 2000 and the serum level of IL-17A or IL-22 in the Yucheng victims....45 Figure 7-1 (Continued) The relation between the predicted serum total TEQ in 2000 and the serum level of IFN-γ or IL-4 in the Yucheng victims....46 Figure 7-2 The relation between the logarithm (base 10) of the predicted serum total TEQ in 2000 and logarithm (base 10) of the serum level of IL-17A or IL-22 in the Yucheng victims....47 Figure 7-2 (Continued) The relation between the logarithm (base 10) of the predicted serum total TEQ in 2000 and logarithm (base 10) of the serum level of IFN-γ or IL-4 in the Yucheng victims....48 Figure 8-1 The relation between the predicted serum total TEQ in 2007 and the serum level of IL-17A or IL-22 in the Yucheng victims....49 Figure 8-1 (Continued) The relation between the predicted serum total TEQ in 2007 and the serum level of IFN-γ or IL-4 in the Yucheng victims....50 Figure 8-2 The relation between the logarithm (base 10) of the predicted serum total TEQ in 2007 and logarithm (base 10) of the serum level of IL-17A or IL-22 in the Yucheng victims....51 Figure 8-2 (Continued) The relation between the logarithm (base 10) of the predicted serum total TEQ in 2007 and logarithm (base 10) of the serum level of IFN-γ or IL-4 in the Yucheng victims....52 Figure 9 Kaplan–Meier product–limit curves for the proportion of patients with positive antibody tests relative to the time of diagnosis of SLE....53 表目錄 Table 1 TH17 cytokine biology in mouse and human....54 Table 2 Age, BMI, education, smoking history, ETS exposure and occupation of the Yucheng women and the control subjects in 2007....55 Table 3 The serum levels of PCBs and PCDD/Fs in the 24 Yucheng victims....56 Table 4 Some autoantibodies detected in SLE patients....57 Table 5 Serological status of ANA in the Yucheng victims and control subjects in 2007....58 Table 6 Serological status of ANA in the 24 Yucheng victims in 2007 (categorized by the serum levels of IL-22)....59 Table 7 Serological status of ANA in all 72 subjects in 2007 (categorized by the serum levels of IL-22)....60 | |
dc.language.iso | en | |
dc.title | 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 | zh_TW |
dc.title | Polychlorinated biphenyls (PCBs)/dibenzofurans (PCDFs) intoxication leads to activation of human T helper 17 cells and increase in serum levels of antinuclear antibody | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳保中,鄭尊仁 | |
dc.subject.keyword | 油症,多氯聯苯,多氯呋,喃,幫手型T細胞17,介白素-17A,介白素-22,全身性紅斑性狼瘡, | zh_TW |
dc.subject.keyword | Yucheng,polychlorinated biphenyls,polychlorinated dibenzofurans,T helper 17 cell,interleukin-17A,interleukin-22,systemic lupus erythematosus, | en |
dc.relation.page | 60 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-16 | |
dc.contributor.author-college | 公共衛生學院 | zh_TW |
dc.contributor.author-dept | 職業醫學與工業衛生研究所 | zh_TW |
顯示於系所單位: | 職業醫學與工業衛生研究所 |
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