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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 胡忠怡(Chung-Yi Hu) | |
dc.contributor.author | Ying-Chun Cho | en |
dc.contributor.author | 卓映君 | zh_TW |
dc.date.accessioned | 2021-06-15T06:18:57Z | - |
dc.date.available | 2015-09-13 | |
dc.date.copyright | 2010-09-13 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-10 | |
dc.identifier.citation | 1. Kindt TJ, Goldsby RA, Osborne BA, Kuby J: Kuby immunology. Edited by New York, W.H. Freeman, 2007
2. Davidson A, Diamond B: Autoimmune diseases, New England Journal of Medicine 2001, 345:340-350 3. Morrow J: Autoimmune rheumatic disease. Edited by Oxford, Oxford University Press, 1999 4. Rahman A, Isenberg DA: Systemic lupus erythematosus, New England Journal of Medicine 2008, 358:929-939 5. Tan EM, Cohen AS, Fries JF, Masi AT, Mcshane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus, Arthritis and Rheumatism 1982, 25:1271-1277 6. Hochberg MC: Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis and Rheumatism 1997, 40:1725 7. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE, Arthritis and Rheumatism 1992, 35:630-640 8. Wakeland EK, Liu K, Graham RR, Behrens TW: Delineating the Genetic Basis of Systemic Lupus Erythematosus, Immunity 2001, 15:397-408 9. Thumboo J, Wee H-L: Systemic lupus erythematosus in Asia: is it more common and more severe?, APLAR Journal of Rheumatology 2006, 9:320-326 10. Huang JL, Yao TC, See LC: Prevalence of pediatric systemic lupus erythematosus and juvenile chronic arthritis in a Chinese population: a nation-wide prospective population-based study in Taiwan, Clinical and Experimental Rheumatology 2004, 22:776-780 11. Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B: Estrogen alters thresholds for B cell apoptosis and activation, The Journal of Clinical Investigation 2002, 109:1625-1633 12. Grimaldi CM: Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells, Current Opinion in Rheumatology 2006, 18:456-461 13. Bhalla AK: Hormones and the immune response, Annals of the Rheumatic Diseases 1989, 48:1-6 14. Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL, Richardson BC: Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice, The Journal of Clinical Investigation 1993, 92:38-53 15. Lu JJ, Chen DY, Hsieh CW, Lan JL, Lin FJ, Lin SH: Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan, Lupus 2007, 16:168-175 16. 林 孝義: 新版 類風濕性關節炎. Edited by 丁淑敏. 台北, 健康文化事業股份有限公司, 2008 17. Joseph A, Brasington R, Kahl L, Ranganathan P, Cheng TP, Atkinson J: Immunologic rheumatic disorders, Journal of Allergy and Clinical Immunology 2010, 125:S204-215 18. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al.: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis, Arthritis and Rheumatism 1988, 31:315-324 19. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH: Rheumatoid Arthritis. Edited by Hetherington P, Ingram J. MOSBY, 2009 20. Zendman AJ, van Venrooij WJ, Pruijn GJ: Use and significance of anti-CCP autoantibodies in rheumatoid arthritis, Rheumatology 2006, 45:20-25 21. Lee DM, Weinblatt ME: Rheumatoid arthritis, The Lancet 2001, 358:903-911 22. Stojanovic R, Vlajinac H, Palic-Obradovic D, Janosevic S, Adanja B: Prevalence of rheumatoid arthritis in Belgrade, Yugoslavia, British Journal of Rheumatology 1998, 37:729-732 23. Spindler A, Bellomio V, Berman A, Lucero E, Baigorria M, Paz S, Garrone N, Torres AI, Romano O, Carraccio A, Leal O, Bazzano A, Vazquez D, Pera O, Arquez G, Valdez M, Lazaro H, Rengel S, Acosta E, Santana M: Prevalence of rheumatoid arthritis in Tucuman, Argentina, Journal of Rheumatology 2002, 29:1166-1170 24. Chou CT, Pei L, Chang DM, Lee CF, Schumacher HR, Liang MH: Prevalence of rheumatic diseases in Taiwan: a population study of urban, suburban, rural differences, Journal of Rheumatology 1994, 21:302-306 25. Dai SM, Han XH, Zhao DB, Shi YQ, Liu Y, Meng JM: Prevalence of rheumatic symptoms, rheumatoid arthritis, ankylosing spondylitis, and gout in Shanghai, China: a COPCORD study, Journal of Rheumatology 2003, 30:2245-2251 26. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ: Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins, Arthritis and Rheumatism 2000, 43:30-37 27. Klareskog L, Catrina AI, Paget S: Rheumatoid arthritis, The Lancet 2009, 373:659-672 28. Balandraud N, Meynard JB, Auger I, Sovran H, Mugnier B, Reviron D, Roudier J,Roudier C: Epstein-Barr virus load in the peripheral blood of patients with rheumatoid arthritis: Accurate quantification using real-time polymerase chain reaction, Arthritis and Rheumatism 2003, 48:1223-1228 29. Toussirot E, Roudier J: Pathophysiological links between rheumatoid arthritis and the Epstein-Barr virus: An update, Joint Bone Spine 2007, 74:418-426 30. Rannou F, François M, Corvol M-T, Berenbaum F: Cartilage breakdown in rheumatoid arthritis, Joint Bone Spine 2006, 73:29-36 31. Ravichandran KS, Lorenz U: Engulfment of apoptotic cells: signals for a good meal, Nat Rev Immunol 2007, 7:964-974 32. Nagata S: Autoimmune diseases caused by defects in clearing dead cells and nuclei expelled from erythroid precursors, Immunological Reviews 2007, 220:237-250 33. Henson PM: Dampening inflammation, Nat Immunol 2005, 6:1179-1181 34. Lauber K, Blumenthal SG, Waibel M, Wesselborg S: Clearance of apoptotic cells: getting rid of the corpses, Molecular Cell 2004, 14:277-287 35. Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S, Xu Y, Autenrieth IB, Schulze-Osthoff K, Belka C, Stuhler G, Wesselborg S: Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal, Cell 2003, 113:717-730 36. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS: Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance, Nature 2009, 461:282-286 37. Schlegel RA, Krahling S, Callahan MK, Williamson P: CD14 is a component of multiple recognition systems used by macrophages to phagocytose apoptotic lymphocytes, Cell Death and Differentiation 1999, 6:583-592 38. Devitt A, Moffatt OD, Raykundalia C, Capra JD, Simmons DL, Gregory CD: Human CD14 mediates recognition and phagocytosis of apoptotic cells, Nature 1998, 392:505-509 39. Fadok VA, Warner ML, Bratton DL, Henson PM: CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3), Journal of Immunology 1998, 161:6250-6257 40. Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH, Kwon TH, Park RW, Kim IS: Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor, Cell Death Differ 2008, 15:192-201 41. Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J: Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment, Nature 2002, 418:200-203 42. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I: Immunosuppressive effects of apoptotic cells, Nature 1997, 390:350-351 43. Munoz L, van Bavel C, Franz S, Berden J, Herrmann M, van der Vlag J: Apoptosis in the pathogenesis of systemic lupus erythematosus, Lupus 2008, 17:371-375 44. Utz, Paul J, Gensler TJ, Anderson P: Death, autoantigen modifications, and tolerance, Arthritis Res 2000, 2:101 - 114 45. Dieker JW, Fransen JH, van Bavel CC, Briand JP, Jacobs CW, Muller S, Berden JH, van der Vlag J: Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus, Arthritis and Rheumatism 2007, 56:1921-1933 46. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S: Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice, Science 2004, 304:1147-1150 47. Hu CY, Wu CS, Tsai HF, Chang SK, Tsai WI, Hsu PN: Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic lupus erythematosus in human, Lupus 2009, 18:676-681 48. Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA: Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase, Journal of Experimental Medicine 2002, 196:135-140 49. Botto M, Dell' Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies, Nature Genetics 1998, 19:56-59 50. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR: Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus, Arthritis and Rheumatism 1998, 41:1241-1250 51. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M: Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus, Arthritis and Rheumatism 2002, 46:191-201 52. Politz O, Gratchev A, McCourt PA, Schledzewski K, Guillot P, Johansson S, Svineng G, Franke P, Kannicht C, Kzhyshkowska J, Longati P, Velten FW, Goerdt S: Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues, Biochemical Journal 2002, 362:155-164 53. Adachi H, Tsujimoto M: FEEL-1, a novel scavenger receptor with in vitro bacteria-binding and angiogenesis-modulating activities, Journal of Biological Chemistry 2002, 277:34264-34270 54. Park SY, Kim SY, Jung MY, Bae DJ, Kim IS: Epidermal growth factor-like domainrepeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance, Mol Cell Biol 2008, 28:5288-5298 55. Jung MY, Park SY, Kim IS: Stabilin-2 is involved in lymphocyte adhesion to the hepatic sinusoidal endothelium via the interaction with alphaMbeta2 integrin, J Leukoc Biol 2007, 82:1156-1165 56. Park SY, Jung MY, Kim IS: Stabilin-2 mediates homophilic cell-cell interactions via its FAS1 domains, FEBS Lett 2009, 583:1375-1380 57. Lee SJ, So IS, Park SY, Kim IS: Thymosin beta4 is involved in stabilin-2-mediated apoptotic cell engulfment, FEBS Lett 2008, 582:2161-2166 58. Park SY, Kang KB, Thapa N, Kim SY, Lee SJ, Kim IS: Requirement of adaptor protein GULP during stabilin-2-mediated cell corpse engulfment, J Biol Chem 2008, 283:10593-10600 59. Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ: The TIM gene family: emerging roles in immunity and disease, Nat Rev Immunol 2003, 3:454-462 60. Kuchroo VK, Dardalhon V, Xiao S, Anderson AC: New roles for TIM family members in immune regulation, Nat Rev Immunol 2008, 8:577-580 61. Umetsu DT, Umetsu SE, Freeman GJ, DeKruyff RH: TIM gene family and their role in atopic diseases, Current Topics in Microbiology and Immunology 2008, 321:201-215 62. Anderson AC, Xiao S, Kuchroo VK: Tim protein structures reveal a unique face for ligand binding, Immunity 2007, 26:273-275 63. Meyers JH, Chakravarti S, Schlesinger D, Illes Z, Waldner H, Umetsu SE, Kenny J, Zheng XX, Umetsu DT, DeKruyff RH, Strom TB, Kuchroo VK: TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation, Nat Immunol 2005, 6:455-464 64. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S: Identification of Tim4 as a phosphatidylserine receptor, Nature 2007, 450:435-439 65. Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM: Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds, Immunity 2007, 27:941-951 66. Rodriguez-Manzanet R, Sanjuan MA, Wu HY, Quintana FJ, Xiao S, Anderson AC, Weiner HL, Green DR, Kuchroo VK: T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice, Proc Natl Acad Sci U S A 2010,107:8706-8711 67. Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ: TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells, Immunity 2007, 27:927-940 68. Pan H-F, Zhang N, Li W-X, Tao J-H, Ye D-Q: TIM-3 as a new therapeutic target in systemic lupus erythematosus, Molecular Biology Reports 2010, 37:395-398 69. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK: The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity, Nat Immunol 2005, 6:1245-1252 70. DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM: T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells, J Immunol 2010, 184:1918-1930 71. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K: Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation, Blood 2009, 113:3821-3830 72. Nishimori H, Shiratsuchi T, Urano T, Kimura Y, Kiyono K, Tatsumi K, Yoshida S, Ono M, Kuwano M, Nakamura Y, Tokino T: A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis, Oncogene 1997, 15:2145-2150 73. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS: BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module, Nature 2007, 450:430-434 74. Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal, Nat Rev Immunol 2005, 5:331-342 75. Kruse K, Janko C, Urbonaviciute V, Mierke C, Winkler T, Voll R, Schett G, Muñoz L, Herrmann M: Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players, Apoptosis 2010 76. Liu G, Wang J, Park YJ, Tsuruta Y, Lorne EF, Zhao X, Abraham E: High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine, J Immunol 2008, 181:4240-4246 77. Matsuzawa D, Hashimoto K, Miyatake R, Shirayama Y, Shimizu E, Maeda K, Suzuki Y, Mashimo Y, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Hata A, Sawa A, Iyo M: Identification of Functional Polymorphisms in the Promoter Region of the Human PICK1 Gene and Their Association With Methamphetamine Psychosis, Am J Psychiatry 2007, 164:1105-1114 78. Mishra PJ, Humeniuk R, Longo-Sorbello GS, Banerjee D, Bertino JR: A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance, Proceedings of the National Academy of Sciences of the United States of America 2007, 104:13513-13518 79. Luers AJ, Loudig OD, Berman JW: MicroRNAs are expressed and processed by human primary macrophages, Cellular Immunology 2010, 263:1-8 80. Hanayama R, Miyasaka K, Nakaya M, Nagata S: MFG-E8-dependent clearance of apoptotic cells, and autoimmunity caused by its failure, Curr Dir Autoimmun 2006, 9:162-172 81. Krysko DV, Vandenabeele P: Phagocytosis of Dying Cells: From Molecular Mechanisms to Human Diseases. Edited by Vandenabeele P. Springer, 2009, p 82. Chae SC, Park YR, Song JH, Shim SC, Yoon KS, Chung HT: The polymorphisms of Tim-1 promoter region are associated with rheumatoid arthritis in a Korean population, Immunogenetics 2005, 56:696-701 83. Nuchnoi P, Ohashi J, Kimura R, Hananantachai H, Naka I, Krudsood S, Looareesuwan S, Tokunaga K, Patarapotikul J: Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria in Thailand, Annals of Human Genetics 2008, 72:327-336 84. Chae SC, Park YR, Shim SC, Yoon KS, Chung HT: The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis, Immunol Lett 2004, 95:91-95 85. Chae SC, Park YR, Lee YC, Lee JH, Chung HT: The association of TIM-3 gene polymorphism with atopic disease in Korean population, Hum Immunol 2004, 65:1427-1431 86. Zhang CC, Wu JM, Cui TP, Wang P, Pan SX: [Study on relationship between polymorphism sites of TIM-3 and allergic asthma in a population of adult Hans from Hubei province of China], Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006, 23:74-77 87. Hayashi A, Nagafuchi H, Ito I, Hirota K, Yoshida M, Ozaki S: Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity, Modern Rheumatology 2009, 19:283-292 88. Urbonaviciute V, Furnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME, Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann M, Voll RE: Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE, J Exp Med 2008, 205:3007-3018 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47794 | - |
dc.description.abstract | 人體中,每天都約有109 以上的細胞會進行細胞凋亡更替以維持身體的恆定性。當細胞發生細胞凋亡以後,會釋放出化學性趨化物質誘使吞噬細胞往凋亡細胞移動。吞噬細胞藉由辨識凋亡細胞上暴露出的“eat-me'訊息分子後,能夠將凋亡細胞吞噬(efferocytosis),並且釋放出抗發炎的細胞激素。若凋亡的細胞無法被即時的清除,就會發生細胞壞死(secondary necrosis)、造成組織處在慢性發炎的狀態,或導致自體免疫疾病的產生。在多個小鼠實驗模型皆証實凋亡細胞清除有缺陷足以造成類似人類狼瘡疾病。為了驗證凋亡細胞清除遲緩與人類自體免疫疾病發生是否相關,本研究探討近年來發現參與凋亡細胞清除相關分子: 包含Stabilin-2、Tim4 (T-cell immunoglobulin and mucin domains-containing protein 4)、Tim3、Tim1、Bai1 (Brain-Specific Angiogenesis Inhibitor1)、HMGB-1 (High mobility group box 1)基因變異性與台灣地區全身性紅斑性狼瘡或類風濕性關節炎罹病之關聯性。
本研究共收集台灣地區136 位全身性紅斑性狼瘡病患與143 位健康對照個案,以及141 位類風濕性關節炎病患和160 位健康對照個案。國人的Tim3、Tim4、HMGB-1 在造成胺基酸改變的基因多型性位點上並未發現變異,以序列特異性寡核苷酸探針雜交或限制酶片段長度多型性方式檢視比較受試檢體之STAB2、BAI1核苷酸多型性之基因型。結果顯示,STAB2 +1529 C/A 位點之A 對偶基因與全身性紅斑性狼瘡罹病為正相關(OR=2.2, 95 % CI=1.1~4.2, p=0.016)。STAB2 +5207 A/C 位點基因型分佈在全身性紅斑性狼瘡病患與對照組雖未達顯著差異(p=0.057),但對偶基因C 攜帶率與全身性紅斑性狼瘡患者發生中樞神經系統病變有顯著正相關(OR=5.0, 95% CI=1.62~15.5, p=0.007)。STAB2 +1529 C/A、STAB2 +5207 A/C 位點與類風性關節成病並不相關。STAB2 +7201-7203 C/G-G/T 單倍體出現率之分佈與全身性紅斑性狼瘡和類風濕性關節炎皆無關。BAI1 基因三端非轉譯區之+5010 G/C位點上C 對偶基因出現率在全身性紅斑性狼瘡及類風濕性關節炎病患呈顯著正相關(SLE: p=0.007, RA: p=0.019)。本研究發現若干參與清除凋亡細胞分子的多型性與國人罹患自體免疫疾病相關聯,暗示凋亡細胞清除遲緩,可能為自體免疫疾病成病原因之一。未來應再進一步檢視STAB2 +1529 C/A 、BAI1 +5010 G/C 位點變異代表的生物分子意義,以確定二者是否有潛力成為國人全身性紅斑性狼瘡或類風濕性關節炎基因標誌。 | zh_TW |
dc.description.abstract | More than 109 cells are undergoing apoptosis in human body daily in the process related to homeostasis maintenance. Apoptotic cells release chemoattractants to attract phagocytes. The recruited phagocytes recognize and engulf apoptotic cells through “eat me”signals presented on apoptotic cells. The so called “efferocytosis” process enhances release of anti-inflammatory cytokines. In case of deficiency in efferocytosis, apoptotic cells undergo secondary necrosis, which result in chronic inflammation in local tissues or auto-immunity. Evidences in several marine models supported that lacking apoptotic cell clearance leads to lupus-like disease. To clarify weather delayed apoptotic cell clearance could contribute to human autoimmune diseases, we intend to investigate the genetic polymorphisms of several efferocytosis related molecules reported in recent years, including Stabilin-2, Tim4 (T-cell immunoglobulin and mucin domains-containing protein 4), Tim1, Tim3, Bai1 (Brain-Specific Angiogenesis Inhibitor 1),and HMGB-1 (High mobility group box 1) and their correlation to systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in Taiwan.
In this study, we studied 136 SLE patients with 143 age, gender-matched non-lupus , and 141 RA patients with 160 age, gender-matched control. There are rare non-synonymous genetic polymorphisms in Tim3, Tim4, and HMGB-1 found in Taiwanese population. The genetic polymorphisms of STAB2 and BAI1 in the studied subjects were examined by PCR/SSOPH (Sequence-specific oilgonucleotide probe hybridization) or PCR/RFLP (Restriction fragment length polymorphisms). We found that carriage of A allele in the STAB2 +1529 C/A locus was significantly associated with SLE (OR=2.2, 95 % CI=1.1~4.2, p=0.016). The genotypic distribution on STAB2 +5207 A/C in SLE and controls did not show significant difference (p=0.057); however, carriage of STAB2 +5207 C allele was positively associated with CNS disorder in SLE patients (OR=5.0, 95 % CI=1.6~15.5, p=0.007). Genotypic variations on STAB2 +1529 and +5207 loci didn’t show significance difference between RA patients and controls. In addition, the haplotype frequency of the STAB2 +7201-7203 C/G-G/T did not show significant difference between SLE or RA patients and their control groups. Moreover, allelic frequency of BAI1 +5010C on BAI1 3’UTR region was positively correlated to both SLE (p=0.007) and RA patients (p=0.019). In the present study, we found several genetic polymorphisms in apoptotic cell clearance related genes were positively associated with autoimmune diseases in Taiwanese population, suggesting apoptotic cell clearance deficiency may be one of the predisposition factor for these diseases. Further study of the altered biological function in STAB2 and BAI1 and the respective genetic polymorphisms would serve to understand and establish them as potential genetic markers for SLE or RA in Taiwanese population. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:18:57Z (GMT). No. of bitstreams: 1 ntu-99-R97424026-1.pdf: 51337103 bytes, checksum: a68d1abd658553c6986d211c567f5f82 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 中文摘要............................................................................ I
Abstract...........................................................................III 第一章 緒論....................................................................... 1 第一節 自體免疫疾病簡介............................................................ 1 第二節 全身性紅斑性狼瘡簡介與文獻探討........................................... 1 2.1 全身性紅斑性狼瘡簡介....................................................... 1 2.2 全身性紅斑性狼瘡臨床診斷與症狀................................................ 2 2.3 全身性紅斑性狼瘡流行病學資料與危險因子........................................ 3 第三節 類風濕性關節炎簡介與文獻探討............................................. 4 3.1 類風濕性關節炎簡介............................................................ 4 3.2 類風濕性關節炎臨床診斷與症狀.................................................. 4 3.3 類風濕性關節炎流行病學資料與危險因子........................................... 5 第四節 凋亡細胞之清除.............................................................. 6 4.1 凋亡細胞清除簡介............................................................... 6 4.2 凋亡細胞清除與自體免疫疾病之關聯性................................................ 8 4.4 簡介 TIM 基因家族................................................................11 4.4.1 TIM4 簡介..................................................................... 12 4.4.2 TIM1 簡介..................................................................... 13 4.4.3 TIM3 簡介....................................................................... 13 4.5 BAI1 簡介........................................................................ 14 4.6 HMGB-1 簡介................................................................................. 15 第五節 基因多型性與生理功能影響.................................................................. 16 第六節 研究目的與實驗設計.............................................................................. 17 第二章 實驗材料與方法............................................................................. 18 第一節 材料.......................................................................................... 18 1.1 檢體收集.................................................................................. 18 1.2 試劑、試藥、試劑套組與工具清單..................................................... 19 1.2.1 試劑試藥清單............................................................................... 19 1.2.2 試劑套組............................................................................. 20 1.2.3 試劑配方...................................................................................... 20 1.2.4 聚合酶連鎖反應之引子序列....................................................... 23 1.2.5 實驗儀器....................................................................................... 25 1.2.6 其他重要耗材............................................................................... 25 1.2.7 軟體與網路工具........................................................................... 26 第二節 實驗方法............................................................................. 26 2.1 檢體 DNA 製備 .......................................................................... 26 2.2 聚合酶連鎖反應引子設計..................................................................... 26 2.3 聚合酶連鎖反應 (Polymerase Chain Reaction, PCR)............................ 27 2.4 聚合酶連鎖反應產物純化與定序......................................................... 27 2.5 序列特異性寡核苷酸探針雜交 (Sequence-specific oligonucleotide probe hybridization, SSOPH).............. 27 2.6 PCR 產物選殖 (TA cloning) ................................................................... 28 2.7 指定點突變 (site-directed Mutagenesis)................................................ 28 2.8 限制酶片段長度多型性 (Restriction fragment length polymorphism, RFLP)............................ 29 2.9 報導基因分析(Reporter assay)................................................................ 29 2.10 統計分析方法........................................................................................ 30 第三章 實驗結果....................................................................................... 31 第一節 STAB2 基因多型性分析.......................................................................... 31 1.1 STAB2 基因多型性前驅測試結果.......................................................... 31 1.2 STAB2 +1529 C/A 之基因多型性與全身性紅斑性狼瘡罹病分析....... 32 1.3 STAB2 +1529 C/A 之基因多型性與類風濕性關節炎罹病分析........... 33 1.4 STAB2 +5207A/C 之基因多型性與全身性紅斑性狼瘡或類風濕性關節炎罹病分析................................... 33 1.5 STAB2 +7201 C/G、+ 7203 G/T 之基因多型性與全身性紅斑性狼瘡或類風濕性關節炎罹病分析..................... 34 第二節 TIM4 基因多型性分析............................................................................ 35 2.1 TIM4 基因多型性前驅性測試結果........................................................ 35 第三節 TIM1 基因多型性分析............................................................................ 35 3.1 TIM1 基因多型性前驅性測試結果........................................................ 35 第四節 TIM3 基因多型性分析............................................................................ 36 4.1 TIM3 基因多型性前驅性測試結果........................................................ 36 第五節 BAI1 基因多型性分析.............................................................................. 36 5.1 BAI1 基因多型性前驅性測試結果......................................................... 36 5.2 BAI1 +5010 G/C 位點之基因多型性與紅斑性狼瘡罹病分析.............. 37 5.3 BAI1 +5010 G/C 位點之基因多型性與類風濕性關節炎罹病分析...... 37 5.4 BAI1 +5010 G/C 位點功能性分析實驗.................................................. 38 第六節 HMGB1 基因多型性分析......................................................................... 39 6.1 HMGB1 基因多型性前驅性測試結果.................................................... 39 第七節 基因多型性與紅斑性狼瘡病患臨床資料分析...................................... 39 第四章 討論................................................................................ 42 第五章 參考資料............................................................................ 48 圖與表..................................................................................... 55 附錄....................................................................................... 87 圖目錄 圖 1 利用序列特異性寡核苷酸雜交法針對 STAB2 +1529 C/A 位點進行分析. ....... 56 圖 2.利用序列特異性寡核苷酸雜交法針對 STAB2 +5207 A/C 位點進行分析......... 57 圖 3 利用序列特異性寡核苷酸雜交法針對 STAB2 +7201C/G、+7203 G/T 位點進行分.............. 59 圖 4 BAI1 +5010 G/C 位點分析實驗結果. ................................................................... 60 圖 5 報導基因分析 BAI1 +5010 C/G 實驗結果.......................................................... 61 表目錄 表 1.實驗個案之年齡與性別分佈................................................................................ 62 表 2.清除凋亡細胞相關基因之前驅測試結果............................................................ 63 表 3 STAB2 +1529 C/A 位點在全身性紅斑性狼瘡病患與對照組之基因型分析..... 65 表 4 STAB2 +1529 C/A 位點在類風濕性關節炎病患與對照組之基因型分析......... 66 表 5 STAB2 +5207 A/C 位點在全身性紅斑性狼瘡病患與對照組之基因型分析...... 67 表 6 STAB2 +5207 A/C 位點在類風濕性關節炎病患與對照組之基因型分析.......... 68 表 7 STAB2 +7201 C/G 在全身性紅斑性狼瘡病患與對照組之基因型分析............. 69 表 8 STAB2 +7201 位點在類風濕性關節炎病患與對照組之基因型分析................. 70 表 9 STAB2 +7203 G/T 位點在全身性紅斑性狼瘡病患與對照組之基因型分析..... 71 表 10 STAB2 +7203 G/T 位點在類風濕性關節炎病患與對照組之基因型分析....... 72 表 11. STAB2 +7201-7203 C/G-G/T 基因多型性在全身性紅斑性狼瘡與對照組分析...... 73 表 12. STAB2 +7201-7203 C/G-G/T 基因多型性在類風濕性關節炎與對照組分析. 74 表 13 BAI1 +5010 G/C 位點在全身性紅斑性狼瘡病患與對照組之基因型分析...... 75 表 14 BAI1+5010 G/C 位點在類風濕性關節炎病患與對照組之基因型分析........... 76 表 15 基因多型性與中樞神經病變症狀分析結果...................................................... 77 表 16 基因多型性與關節炎症狀分析結果.................................................................. 78 表 17 基因多型性與漿膜炎症狀分析結果.................................................................. 79 表 18 基因多型性與腎炎症狀分析結果...................................................................... 80 表 19 基因多型性與白血球低下分析結果.................................................................. 81 表 20 基因多型性與血小板低下分析結果.................................................................. 82 表 21 基因多型性與抗 DNA 抗體分析結果 ............................................................... 83 表 22 基因多型性與抗細胞核抗體分析結果.............................................................. 84 表 23 基因多型性與補體低下分析結果...................................................................... 85 表 24 基因多型性與抗心磷酯分析結果...................................................................... 86 | |
dc.language.iso | zh-TW | |
dc.title | 凋亡細胞清除相關基因多型性與台灣地區全身性紅斑性狼瘡及類風濕性關節炎發生之探討 | zh_TW |
dc.title | Investigating of Genetic Polymorphisms on Apoptotic Cells Clearance-Related Genes in Systemic Lupus Erythematosus and Rheumatoid Arthritis in Taiwanese Population | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 許秉寧(Ping-Ning Hsu),莊雅惠(Ya-Hui Chuang) | |
dc.subject.keyword | 凋亡細胞清除,全身性紅斑性狼,瘡,類,風濕性關節炎,核苷,酸多型性,Stabilin-2,Bai1, | zh_TW |
dc.subject.keyword | Efferocytosis,Systemic Lupus Erythematosus (SLE),Rheumatoid Arthritis (RA),Genetic polymorphisms,Stabilin-2,Bai1, | en |
dc.relation.page | 111 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-08-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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