請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72487
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 廖述朗(Shu-Lang Liao) | |
dc.contributor.author | Chih-Chung Lin | en |
dc.contributor.author | 林志忠 | zh_TW |
dc.date.accessioned | 2021-06-17T06:59:47Z | - |
dc.date.available | 2019-08-26 | |
dc.date.copyright | 2019-08-26 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-05 | |
dc.identifier.citation | Antonelli A, Saracino A, Alberti B, et al. High-dose intravenous immunoglobulin treatment in Graves' ophthalmopathy. Acta Endocrinol (Copenh) 1992;126:13-23.
Artlett CM, Thacker JD. Molecular activation of the NLRP3 Inflammasome in fibrosis: common threads linking divergent fibrogenic diseases. Antioxidants & redox signaling 2015;22:1162-75. Bahn RS. Current Insights into the Pathogenesis of Graves’Ophthalmopathy. Horm Metab Res 2015;47:773-8. Bahn RS. Graves' ophthalmopathy. N Engl J Med 2010;362:726-38. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329:1468-75. Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid 2008;18:333-46. Bartley GB, Fatourechi V, Kadrmas EF, et al. Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology 1996;103:958-62. Bednarczuk T, Gopinath B, Ploski R, Wall JR. Susceptibility genes in Graves‘ ophthalmopathy: searching for a needle in a haystack? Clin Endocrinol (Oxf) 2007;67:3-19. Chang TC, Liao SL. Slow-release lanreotide in Graves' ophthalmopathy: A double-blind randomized, placebocontrolled clinical trial. J Endocrinol Invest 2006;29:413-22. Chen B, Tsui S, Smith TJ. IL-1 beta induces IL-6 expression in human orbital fibroblasts: identification of an anatomic-site specific phenotypic attribute relevant to thyroid-associated ophthalmopathy. J Immunol 2005;175:1310-9. Davies TF, Teng CS, McLachlan SM, Smith BR, Hall R. Thyrotropin receptors in adipose tissue, retro-orbital tissue and lymphocytes. Mol Cell Endocrinol 1978;9: 303-10. Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual review of immunology 2011;29:707-35. Dickinson AJ, Vaidya B, Miller M, et al. Double-blind, placebo-controlled trial of octreotide long-acting repeatable(LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2004;89:5910-5. Eckstein AK, Losch C, Glowacka D, et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol 2009;93:1052-6. Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L, Zhong S, Liu X, Li D, Liang R et al. IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO. J Clin Endocrinol Metab 2016;101:2955-65. Feldon SE, Park DJ, O'Loughlin CW, et al. Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy. Invest Ophthalmol Vis Sci 2005;46:3913-21. Finamor FE, Martins JR, Nakanami D, Paiva ER, Manso PG, Furlanetto RP. Pentoxifylline (PTX)--an alternative treatment in Graves' ophthalmopathy (inactive phase): assessment by a disease specific quality of life questionnaire and by exophthalmometry in a prospective randomized trial. Eur J Ophthalmol 2004;14:277-83. Gianoukakis AG, Khadavi N, Smith TJ. Cytokines, Graves' disease, and thyroid-associated ophthalmopathy. Thyroid 2008;18:953-8. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. The Journal of experimental medicine 2007;204:2803-12. Hosokawa Y, Hosokawa I, Ozaki K, Nakae H, Matsuo T. Interleukin (IL)-17A synergistically enhances CC chemokine ligand 20 production in IL-1beta-stimulated human gingival fibroblasts. Human immunology 2012;73:26-30. Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Annals of the rheumatic diseases 2011;70:727-32. Hwang CJ, Afifiyan N, Sand D, Naik V, Said J, et al. Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1. Invest Ophthalmol Vis Sci 2009;50:2262-8. Kahaly G, Pitz S, Muller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol 1996;106:197-202. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40. Kanneganti TD, Lamkanfi M, Kim YG, et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 2007;26:433-43. Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol 2003;163:1291-300. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397-411. Lee WM, Paik JS, Cho WK, Oh EH, Lee SB, Yang SW. Rapamycin enhances TNF-alpha-induced secretion of IL-6 and IL-8 through suppressing PDCD4 degradation in orbital fibroblasts. Curr Eye Res 2013;38:699-706. Li X, Qi Y, Ma X, Huang F, Guo H, Jiang X, Hong J, Lin D, Cui B, Ning G et al. Chemokine (C-C motif) ligand 20, a potential biomarker for Graves' disease, is regulated by osteopontin. PloS one 2013;8:e64277. Liu X, Leung S, Wang C, Tan Z, Wang J, Guo TB, Fang L, Zhao Y, Wan B, Qin X, Lu L, Li R, Pan H, Song M, Liu A, Hong J, Lu H, Zhang JZ. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med. 2010;16:191-7. Madaschi S, Rossini A, Formenti I, et al. Treatment of thyroid-associated orbitopathy with rituximab-a novel therapy for an old disease: case report and literature review. Endocr Pract 2010;16:677-85. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417-26. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009;27:229-65. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-79. Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye (Lond) 2005;19:1286-9. Perros P, Weightman DR, Crombie AL, Kendall-Taylor P. Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh) 1990;122:8-12. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves' disease and ophthalmopathy. Endocr Rev 2003;24:802-35. Rock KL, Kataoka H, Lai JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 2013;9:13-23. Salvi M, Vannucchi G, Campi I, et al. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007;156:33-40. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017;376:1748-61. Smith TJ. Pathogenesis of Graves' orbitopathy: a 2010 update. J Endocrinol Invest 2010;33:414-21. Smith TJ. The putative role of fibroblasts in the pathogenesis of Graves' disease: evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation. Autoimmunity 2003;36:409-15. So A, Ives A, Joosten LA, Busso N. Targeting inflammasomes in rheumatic diseases. Nat Rev Rheumatol 2013;9:391-9. Stamato FJ, Maciel RM, Manso PG, et al. Colchicine in the treatment of the inflammatory phase of Graves' ophthalmopathy: a prospective and randomized trial with prednisone. Arq Bras Oftalmol 2006;69:811-6. Stan MN, Garrity JA, Bradley EA, et al. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves' ophthalmopathy. J Clin Endocrinol Metab 2006;91:4817-24. Starkey KJ, Janezic A, Jones G, Jordan N, Baker G, Ludgate M. Adipose thyrotrophin receptor expression is elevated in Graves' and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J Mol Endocrinol 2003;30:369-80. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature 2012;481:278-86. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009;31:331-41. Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The role of IL-17 and Th17 lymphocytes in autoimmune diseases. Arch Immunol Ther Exp 2015;63:435-49. Tsai CC, Wu SB, Cheng CY, Kao SC, Kau HC, Chiou SH, Hsu WM, Wei YH. Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves' ophthalmopathy: evidence that oxidative stress has a role in this disorder. Eye 2010;24:1520-5. Tsai CC, Wu SB, Cheng CY, Kao SC, Kau HC, Lee SM, Wei YH. Increased response to oxidative stress challenge in Graves' ophthalmopathy orbital fibroblasts. Molecular vision 2011;17:2782-8. Tseng WA, Thein T, Kinnunen K, et al. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54:110-120. van de Veerdonk FL, Smeekens SP, Joosten LA, et al. Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease. Proc Natl Acad Sci U S A 2010;107:3030-3. van Steensel L, van Hagen PM, Paridaens D, Kuijpers RW, et al. Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy. Br J Ophthalmol. 2011;95:735-8. Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves' ophthalmopathy patients. Clin Endocrinol (Oxf) 2003;58:280-7. Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Investigative ophthalmology & visual science 2014;55:1735-48. Wei Jin, Chen Dong. IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect. 2013;2:e60. Wemeau JL, Caron P, Beckers A, et al. Octreotide (long-acting release formulation) treatment in patients with graves' orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab 2005;90:841-8. Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves' ophthalmopathy and onset of thyroidal Graves' disease. J Endocrinol Invest 1988;11:615-9. Zhang S, Yu N, Zhang R, Zhang S, Wu J. Interleukin-17A Induces IL-1beta Secretion From RPE Cells Via the NLRP3 Inflammasome. Invest Ophthalmol Vis Sci 2016;57:312-9. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010;11:136-40. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72487 | - |
dc.description.abstract | 研究目的:
葛瑞芙氏眼病變Graves’ ophthalmopathy (簡稱GO) 和自體免疫疾病相關聯。病變位於眼窩脂肪、結締組織及眼外肌,臨床表現為眼瞼攣縮、突眼、眼周水腫、眼外肌活動受限等,然而葛瑞芙氏眼病變的致病機轉至今尚未完全明瞭。 最近的研究發現,白細胞介素17A (Interleukin-17A, IL-17A)、發炎體和相關的發炎細胞激素可能在葛瑞芙氏眼病變的自體免疫上參與其中。因此,我們設法瞭解IL-17A和NLRP3發炎體在葛瑞芙氏眼病變致病機轉中所扮演之角色,以提供將來治療的新方向。 研究方法: 葛瑞芙氏眼病變患者和非葛瑞芙氏眼病變者各30名,前者為GO實驗組,後者為對照組,取其眼窩脂肪結締組織當作實驗檢體,並進行眼窩纖維母細胞培養。比較兩組之NLRP3發炎體免疫組織化學染色 (immunohistochemical staining);以IL-17A刺激纖維母細胞後,利用即時反轉錄聚合酶鏈鎖反應 (real-time RT-PCR)、西方墨點法 (Western blot)、及酵素連結免疫吸附法 ( ELISA) 分析兩組pro- IL-1β、IL-1β、NLRP3及caspase-1濃度變化。 接著在眼窩纖維母細胞培養中加入caspase-1抑制劑,並使用小分子干擾核糖核酸 (siRNA) knockdown NLRP3發炎體後,觀察兩組相關細胞激素 (cytokine) 變化情形。統計分析方法為One-way ANOVA及2-tailed Student’s t tests。 研究結果: 免疫組織化學染色及細胞培養染色顯示在葛瑞芙氏眼病變患者的眼窩結締組織中相較於健康對照組,有較明顯的NLRP3發炎體表現。IL-17A能誘導GO眼窩纖維母細胞增加pro- IL-1β mRNA表現及白細胞介素1β (IL-1β) 蛋白質濃度。此外,IL-17A能活化caspase-1及NLRP3發炎體表現,表示NLRP3發炎體的激活和IL-17A息息相關。 再者,我們使用caspase-1的專一抑制劑Z-YVAD-fmk,發現其能有效抑制IL-1β分泌,且和它的濃度呈正相關性。當siRNA轉染 (transfection) 纖維母細胞,能夠向下調節NLRP3 mRNA及蛋白質的表現。同時,NLRP3發炎體的knockdown也顯著地抑制IL-17A所調節之pro-IL-1β表現量。 結論: 我們的研究發現IL-17A能夠透過眼窩纖維母細胞NLRP3發炎體的活化,刺激IL-1β的生成,進而促進相關發炎細胞激素分泌,導致後續自體免疫發展和葛瑞芙氏眼病變的形成。同時,也給予我們未來治療葛瑞芙氏眼病變藥物發展之新線索。 | zh_TW |
dc.description.abstract | Objective:
The development of Graves’ ophthalmopathy (GO) is associated with autoimmune dysfunction. Recent findings in GO indicate that IL-17A, inflammasome and related cytokines may also be involved in the autoimmunity of GO. We sought to investigate the pathogenic functions of IL-17A and NLRP3 inflammasome in GO. Methods: Orbital fat specimens were collected from 30 GO patients and 30 Non-GO controls. Immunohistochemical staining of orbital fat tissues and cell cultures of orbital fibroblasts were conducted in GO and Non-GO groups. Then, IL-17A was added to the fibroblast cultures, and cytokine expression, signaling pathways, and inflammasome mechanism were investigated using real-time RT-PCR, ELISA, Western blot, and small interfering RNA (siRNA). Results: Immunohistochemical staining of orbital fat specimen showed more expression of NLRP3 in orbital tissue of GO, compared with normal subjects. Interleukin-17A upregulated the mRNA levels of pro-IL-1β and the protein level of IL-1β in GO group. Furthermore, IL-17A was validated to enhance caspase-1 and NLRP3 protein expression in orbital fibroblasts, suggesting NLRP3 inflammasome activation. Inhibiting caspase-1 activity could also decrease IL-1β secretion. When siRNA transfected the orbital fibroblasts, NLRP3 expression was knockdown significantly and IL-17A-mediated pro-IL-1β mRNA release was also downregulated. Conclusions: Our observations illustrate that IL-17A could promote IL-1β production from orbital fibroblasts via the NLRP3 inflammasome in Graves’ ophthalmopathy, and subsequent cytokines may induce more inflammation and autoimmunity. This gives us the clues to target therapeutic potential for GO in the future. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T06:59:47Z (GMT). No. of bitstreams: 1 ntu-108-P06421009-1.pdf: 1680906 bytes, checksum: 80ba7e14a51ed3f940f0f0453016f625 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii 英文摘要 v 一、緒論 1 1.1 葛瑞芙氏症簡介 1 1.2 葛瑞芙氏眼病變簡介 1 1.3 葛瑞芙氏眼病變之致病機轉 2 1.4 研究動機與目的 4 二、研究方法與材料 7 2.1 樣本收集及實驗方法 7 2.1.1 研究對象 7 2.1.2 檢體收集 7 2.1.3 免疫組織化學染色 (immunohistochemical staining) 7 2.1.4 即時反轉錄聚合酶鏈鎖反應 (real-time RT-PCR) 8 2.1.5 西方墨點法 (Western blot) 8 2.1.6 酵素連結免疫吸附法 (Enzyme-linked immunosorbent assay) 9 2.1.7 眼窩纖維母細胞培養 9 2.2 IL-17A活化NLRP3及IL-1β研究 10 2.2.1 RT-PCR檢測IL-17A刺激下標的物mRNA表現 10 2.2.2 ELISA檢測IL-17A刺激下IL-1β濃度 10 2.2.3 Western blot檢測IL-17A刺激下標的物蛋白質濃度 10 2.2.4 ELISA檢測caspase-1抑制劑作用 10 2.3 NLRP3發炎體功能研究 11 2.3.1 RT-PCR檢測NLRP3 knockdown標的物mRNA 11 2.3.2 Western blot檢測NLRP3 knockdown之表現 11 2.4 統計方法 11 三、結果 12 3.1 NLRP3發炎體表現於葛瑞芙氏眼病變眼窩纖維母細胞 12 3.2 IL-17A能誘導眼窩纖維母細胞分泌IL-1β 12 3.3 IL-17A能活化眼窩纖維母細胞的NLRP3發炎體 12 四、討論 14 4.1 Th17與IL-17A關於GO的研究及重要性 14 4.2 NLRP3發炎體和GO致病機轉相關性 15 4.3 IL-1β在GO的角色 16 4.4 現今葛瑞芙氏眼病變治療及未來發展 17 4.5 本實驗的限制 19 五、展望 20 5.1 基礎研究的展望 20 5.2 臨床層面的展望 20 六、英文簡述 21 七、參考文獻 27 八、圖表 35 | |
dc.language.iso | zh-TW | |
dc.title | 白細胞介素17A和NLRP3發炎體在葛瑞芙氏眼病變致病機轉中所扮演之角色 | zh_TW |
dc.title | The Role of Interleukin-17A and NLRP3 Inflammasome in the Pathogenesis of Graves' Ophthalmopathy | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 楊偉勛,施翔蓉 | |
dc.subject.keyword | 葛瑞芙氏眼病變,甲狀腺眼疾,白細胞介素17A,NLRP3發炎體,白細胞介素1β, | zh_TW |
dc.subject.keyword | Graves’ ophthalmopathy,IL-17A,NLRP3 inflammasome,IL-1β, | en |
dc.relation.page | 45 | |
dc.identifier.doi | 10.6342/NTU201902527 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 1.64 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。