請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22184
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
dc.contributor.author | Ling-En Huang | en |
dc.contributor.author | 黃鈴恩 | zh_TW |
dc.date.accessioned | 2021-06-08T04:13:32Z | - |
dc.date.copyright | 2010-09-09 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-16 | |
dc.identifier.citation | 1. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002;2(5):364-71.
2. Mount C, Featherstone J. Rheumatoid arthritis market. Nat Rev Drug Discov. 2005;4(1):11-2. 3. Oliver JE, Silman AJ. Why are women predisposed to autoimmune rheumatic diseases? Arthritis Res Ther. 2009;11(5):252. PMCID: 2787267. 4. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003;426(6965):454-60. 5. Feldmann M, Maini SR. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev. 2008;223:7-19. 6. Biesiada L, Krasomski G, Tchorzewski H. [Current opinions on immunological processes in rheumatoid arthritis during pregnancy]. Pol Merkur Lekarski. 2001;10(60):477-9. 7. Cutolo M, Villaggio B, Seriolo B, Montagna P, Capellino S, Straub RH, et al. Synovial fluid estrogens in rheumatoid arthritis. Autoimmun Rev. 2004;3(3):193-8. 8. Cunningham MW, Antone SM, Gulizia JM, McManus BM, Fischetti VA, Gauntt CJ. Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin. Proc Natl Acad Sci U S A. 1992;89(4):1320-4. PMCID: 48441. 9. Olson JK, Croxford JL, Miller SD. Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease. Viral Immunol. 2001;14(3):227-50. 10. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9(4):246-58. PMCID: 2854652. 11. Nathan C. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest. 2003;111(6):769-78. PMCID: 153776. 12. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173-82. 13. Haynes DR. Inflammatory cells and bone loss in rheumatoid arthritis. Arthritis Res Ther. 2007;9(3):104. PMCID: 2206339. 14. Mohr W, Menninger H. Polymorphonuclear granulocytes at the pannus-cartilage junction in rheumatoid arthritis. Arthritis Rheum. 1980;23(12):1413-14. 15. Cedergren J, Forslund T, Sundqvist T, Skogh T. Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients. J Rheumatol. 2007;34(11):2162-70. 16. Sassi ML, Aman S, Hakala M, Luukkainen R, Risteli J. Assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) unlike CrossLaps assay reflects increased pathological degradation of type I collagen in rheumatoid arthritis. Clin Chem Lab Med. 2003;41(8):1038-44. 17. Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis. 2005;64(2):196-201. PMCID: 1755350. 18. Chakravarti A, Raquil MA, Tessier P, Poubelle PE. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood. 2009;114(8):1633-44. 19. Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med. 2005;11(9):936-43. 20. Jakus Z, Simon E, Frommhold D, Sperandio M, Mocsai A. Critical role of phospholipase Cgamma2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis. J Exp Med. 2009;206(3):577-93. PMCID: 2699137. 21. Kraan MC, de Koster BM, Elferink JG, Post WJ, Breedveld FC, Tak PP. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Arthritis Rheum. 2000;43(7):1488-95. 22. Bakker AB, Baker E, Sutherland GR, Phillips JH, Lanier LL. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc Natl Acad Sci U S A. 1999;96(17):9792-6. PMCID: 22289. 23. Lanier LL, Bakker AB. The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol Today. 2000;21(12):611-4. 24. Campbell KS, Colonna M. DAP12: a key accessory protein for relaying signals by natural killer cell receptors. Int J Biochem Cell Biol. 1999;31(6):631-6. 25. Chen ST, Lin YL, Huang MT, Wu MF, Cheng SC, Lei HY, et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature. 2008;453(7195):672-6. 26. Gingras MC, Lapillonne H, Margolin JF. TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development. Mol Immunol. 2002;38(11):817-24. 27. Aoki N, Zganiacz A, Margetts P, Xing Z. Differential regulation of DAP12 and molecules associated with DAP12 during host responses to mycobacterial infection. Infect Immun. 2004;72(5):2477-83. PMCID: 387866. 28. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7(2):131-7. 29. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783-801. 30. Crocker PR. Siglecs in innate immunity. Curr Opin Pharmacol. 2005;5(4):431-7. 31. Nataf S, Anginot A, Vuaillat C, Malaval L, Fodil N, Chereul E, et al. Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am J Pathol. 2005;166(1):275-86. PMCID: 1602283. 32. Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest. 2003;111(3):323-32. PMCID: 151867. 33. Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428(6984):758-63. 34. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164(10):4991-5. 35. Humphrey MB, Daws MR, Spusta SC, Niemi EC, Torchia JA, Lanier LL, et al. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. J Bone Miner Res. 2006;21(2):237-45. 36. Kuai J, Gregory B, Hill A, Pittman DD, Feldman JL, Brown T, et al. TREM-1 expression is increased in the synovium of rheumatoid arthritis patients and induces the expression of pro-inflammatory cytokines. Rheumatology (Oxford). 2009;48(11):1352-8. 37. Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, et al. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med. 2003;198(4):669-75. PMCID: 2194176. 38. Inui M, Kikuchi Y, Aoki N, Endo S, Maeda T, Sugahara-Tobinai A, et al. Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12. Proc Natl Acad Sci U S A. 2009;106(12):4816-21. PMCID: 2660769. 39. Joyce-Shaikh B, Bigler ME, Chao CC, Murphy EE, Blumenschein WM, Adamopoulos IE, et al. Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J Exp Med. 2010;207(3):579-89. PMCID: 2839155. 40. Nakamura H, Ueki Y, Sakito S, Matsumoto K, Yano M, Miyake S, et al. High serum and synovial fluid granulocyte colony stimulating factor (G-CSF) concentrations in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2000;18(6):713-8. 41. Campbell IK, Rich MJ, Bischof RJ, Hamilton JA. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J Leukoc Biol. 2000;68(1):144-50. 42. Miyahara H, Hotokebuchi T, Saikawa I, Arita C, Takagishi K, Sugioka Y. The effects of recombinant human granulocyte colony-stimulating factor on passive collagen-induced arthritis transferred with anti-type II collagen antibody. Clin Immunol Immunopathol. 1993;69(1):69-76. 43. Lawlor KE, Campbell IK, Metcalf D, O'Donnell K, van Nieuwenhuijze A, Roberts AW, et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc Natl Acad Sci U S A. 2004;101(31):11398-403. PMCID: 509212. 44. Kelchtermans H, Struyf S, De Klerck B, Mitera T, Alen M, Geboes L, et al. Protective role of IFN-gamma in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production. J Leukoc Biol. 2007;81(4):1044-53. 45. Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P. Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J Immunol. 1997;158(11):5507-13. 46. Zhang X, Majlessi L, Deriaud E, Leclerc C, Lo-Man R. Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity. 2009;31(5):761-71. 47. Laffafian I, Hallett MB. Does cytosolic free Ca2+ signal neutrophil chemotaxis in response to formylated chemotactic peptide? J Cell Sci. 1995;108 ( Pt 10):3199-205. 48. Neu B, Wenby R, Meiselman HJ. Effects of dextran molecular weight on red blood cell aggregation. Biophys J. 2008;95(6):3059-65. PMCID: 2527284. 49. Issekutz AC, Issekutz TB. Quantitation and kinetics of polymorphonuclear leukocyte and lymphocyte accumulation in joints during adjuvant arthritis in the rat. Lab Invest. 1991;64(5):656-63. 50. Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43(2):250-8. 51. Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265(1):144-50. 52. Shigeyama Y, Pap T, Kunzler P, Simmen BR, Gay RE, Gay S. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 2000;43(11):2523-30. 53. Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, et al. The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis Rheum. 2001;44(12):2768-76. 54. Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P. Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem. 2001;276(23):20659-72. 55. Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, et al. Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis. 2002;61(12):1047-54. PMCID: 1753975. 56. Poubelle PE, Chakravarti A, Fernandes MJ, Doiron K, Marceau AA. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther. 2007;9(2):R25. PMCID: 1906801. 57. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: 'N1' versus 'N2' TAN. Cancer Cell. 2009;16(3):183-94. 58. Wipke BT, Allen PM. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol. 2001;167(3):1601-8. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22184 | - |
dc.description.abstract | Rheumatoid arthritis is a chronic systemic autoimmune disease which is characterized by synovitis. And it will gradually develop into poly-articular arthritis with the passage of time. The manifest symptoms of rheumatoid arthritis are joint pain; swelling; stiffness; deformation, moreover, the most prominent symptoms are joint swelling and pain. In late stages of RA, deformity of joint and defective joints expanded due to severely damage. Hence, patient could not be self-management further cause adverse effects in family and society. Rheumatoid arthritis processes involving dys-regulation of multiple components of immune system including the adaptive and the innate immune system. Compared to adaptive immunity, the role of innate immunity in the pathogenesis of rheumatoid arthritis is not well being elucidated yet.
C-type lectin is as an effector molecule in the innate immune system, expressed on immune cells specifically. MDL-1 /CLEC5A is a type II trans-membrane protein belonging to the C type lectin superfamily. According to previous publications, MDL-1 be found participate in osteoclastogenesis when partnered with DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages in mice. Moreover, In animal model of rheumatoid arthritis shows that MDL-1 as key regulator of synovial injury and bone erosion during Rheumatoid Arthritis joint inflammation. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the incidence and severity of autoimmune joint inflammation in mice. Neutrophils presence extraordinary numbers in the synovial fluid of patients with RA when disease flares up. But whether MDL-1 could be detect on neutrophil in RA synovial fluid or whether MDL-1 could modulate neutrophil function are uncertainly. Our data displays neutrophils from synovial fluid in RA patients the MDL-1 expression increased compared with the neutrophil from healthy volunteers peripheral blood. This observation also exist in AS and Gout patient. Therefore, immunehistochemical analyses disclosed MDL-1 positive cells in human RA synovial tissue but not in Osteoarthritis (OA) synovial tissue. Further investigation supporting that MDL-1 expression could be promoted by G-CSF in the present of TNF-α which cytokines are related to RA and neutrophil. Although anti-MDL-1 mAb did not have capacity to stimulate neutrophil to secrete TNF-α and IL-10, TLR4 ligands has been shown to stimulate the raise of RANKL on neutrophil in the present of anti-MDL-1 mAb. Moreover, RANKL could promote osteoclastogenesis. In our results show MDL-1 could enhance Ca2+ influx on neutrophil and enhance generation of neutrophil chemotactic activities. All of evidences indicate MDL-1 have some capacity to modulate the pathogenesis of rheumatoid arthritis. The aim and contribution of this research are to investigate what kind of function mediated by MDL-1 on neutrophil in Rheumatoid arthritis. In the future, expecting that apply MDL-1 related molecule to pharmacological application in RA therapy and further improve patient’s quality of life. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:13:32Z (GMT). No. of bitstreams: 1 ntu-99-R96b42022-1.pdf: 3609967 bytes, checksum: 3b9a22186148700e431c890059e92393 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 口試委員會審定書----------------------------------------------------ii
目錄--------------------------------------------------------------- iii 縮寫表--------------------------------------------------------------v 中文摘要------------------------------------------------------------1 英文摘要------------------------------------------------------------3 第一章 緒論 1.1類風濕關節炎-------------------------------------------------6 1.2嗜中性白血球與類風濕性關節炎---------------------------------8 1.3 MDL-1/CLEC5A------------------------------------------------10 1.4 MDL-1/CLEC5A與類風濕關節炎----------------------------------11 第二章 實驗目的及貢獻----------------------------------------------14 第三章 材料與方法--------------------------------------------------16 第四章結果 4.1 類風溼性關節炎關節液中含有大量的嗜中性白血球----------------29 4.2 MDL-1高量的表現在類風濕性關節炎患者的嗜中性白血球表面-------29 4.3 MDL-1表現在類風溼性關節炎患者的關節滑膜組織-----------------30 4.4 MDL-1在嗜中性白血球表面的表達可經由G-CSF加TNF-α所誘導----30 4.5 TLR 2、TLR 4、TLR 5配體可以刺激嗜中性白血球產生活性氧化物------32 4.6在類風濕性關節炎滑膜液的嗜中性白血球無法經MDL-1與TLR訊號協同 作用使之分泌TNF-α或IL-10----------------------------------33 4.7嗜中性白血球經由TLR4和MDL - 1的刺激有助於其表面表現RANKL----35 4.8 嗜中性白血球經由MDL - 1的訊號可促進細胞內鈣離子流動---------36 4.9 嗜中性白血球經由MDL - 1的訊號而增強其趨化作用--------------37 第五章 討論--------------------------------------------------------39 第六章 結論--------------------------------------------------------48 參考文獻-----------------------------------------------------------51 圖表 --------------------------------------------------------------59 | |
dc.language.iso | zh-TW | |
dc.title | 嗜中性白血球上MDL-1(CLEC5A)在類風性關節炎中的角色 | zh_TW |
dc.title | The role of MDL-1(CLEC5A) on neutrophil in Rheumatoid Arthritis | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 謝世良(Shie-Liang Hsieh) | |
dc.contributor.oralexamcommittee | 司徒惠康(Huey-Kang Sytwu) | |
dc.subject.keyword | 類風濕性關節炎,嗜中性白血球,C-型凝集素,MDL-1(CLEC5A),類鐸受體, | zh_TW |
dc.subject.keyword | Rheumatoid arthritis,Neutrophil,C-type lectin,MDL-1(CLEC5A),Toll like receptor, | en |
dc.relation.page | 79 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-99-1.pdf 目前未授權公開取用 | 3.53 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。