臺灣博碩士論文加值系統

目錄
指導教授推薦書
口試委員會審定書
誌謝 iii
中文摘要 iv
Abstract v
目錄 vi
圖目錄 ix
附錄目錄 xi
第一章 背景 1
1.1 自體免疫葡萄膜炎 1
1.2 實驗性自體免疫葡萄膜炎 2
1.3 視網膜色素上皮細胞 8
1.4 TLR與自體免疫性疾病 12
1.5 研究動機與實驗設計 16
第二章 研究方法與材料 17
2.1 小鼠primary RPE細胞培養 17
2.2 小鼠primary RPE細胞RNA萃取並反轉錄為cDNA 17
2.3 即時定量聚合酶鏈鎖反應(real-time quantitative polymerase chain reaction, qPCR) 18
2.4 細胞免疫螢光染色 19
2.5 Active immunization葡萄膜炎動物模式 19
2.6 Adoptive transfer葡萄膜炎動物模式 19
2.7 製備脾臟細胞懸浮液 20
2.8 Nylon wool CD3+細胞純化 20
2.9 小鼠周邊血採集與前處理 21
2.10 細胞外染色 21
2.11 細胞內染色 21
2.12 Enzyme-linked immunosorbent assay, ELISA 22
2.13 石蠟包埋與切片 23
2.14 Hematoxylin and eosin染色 23
2.15 統計方法 24
第三章 結果 25
3.1 分析EAU小鼠primary RPE之TLRs基因表現 25
3.1.1 從小鼠眼睛分離RPE細胞並培養 25
3.1.2 檢測aEAU小鼠tlr基因表現差異 26
3.1.3 建立tEAU小鼠動物模式 27
3.1.4 分析EAU小鼠中RPE細胞tlr基因表現量之差異 29
3.2 探討TLR7活化對於tEAU小鼠疾病發展之影響 30
3.3 評估TLR7 antagonist在tEAU小鼠的療效 32
3.4 探討在抑制TLR7的治療中，RPE細胞所扮演的角色 34
3.4.1 檢測in vitro環境下給予TLR7刺激對pRPE產生發炎因子之影響 34
3.4.2 觀察in vitro環境下給予TLR7 antagonist對pRPE產生發炎因子之影響 35
第四章 討論 36
第五章 參考文獻 43
附圖 55
附錄 83


 
圖目錄
圖一 在解剖顯微鏡下分離出小鼠RPE細胞並進行體外培養 55
圖二 以mRPE65確認初代培養RPE細胞的純度 56
圖三 aEAU小鼠之疾病進程與嚴重程度 57
圖四 aEAU小鼠RPE細胞tlr基因表現比較 58
圖五 tEAU小鼠動物模式建立之實驗設計和其疾病進程 59
圖六 以FACS分析tEAU小鼠脾臟之免疫細胞分群 60
圖七 分析tEAU小鼠表現IL-17和IFN-γ之免疫細胞族群 61
圖八 分析tEAU小鼠經IRBP刺激後會表現IL-17和IFN-γ之免疫細胞族群 62
圖九 分析tEAU小鼠脾臟細胞經IRBP刺激後分泌IL-17和IFN-γ的量 63
圖十 以組織病理切片評估EAU小鼠眼睛發炎情形 64
圖十一 觀察RPE細胞在aEAU和tEAU動物模式之tlr基因表現量差異 65
圖十二 評估小鼠葡萄膜炎疾病嚴重程度與tlr基因表現量之關聯性 66
圖十三 評估給予TLR7 agonist R848對於tEAU小鼠疾病進程之影響 67
圖十四 分析給予TLR7 agonist R848後之tEAU小鼠其可表現IL-17和IFN-γ之免疫細胞族群 69
圖十五 分析給予TLR7 agonist R848後之tEAU小鼠其脾臟細胞中之調控型T細胞族群 71
圖十六 分析給予TLR7 agonist R848後之tEAU小鼠其脾臟細胞經IRBP刺激後所分泌之IL-17和IFN-γ 72
圖十七 分析給予TLR7 agonist R848後之tEAU小鼠其RPE細胞TLR7之基因表現 73
圖十八 評估給予TLR7 antagonist Hydroxychloroquine對於tEAU小鼠疾病進程之影響 74
圖十九 分析給予TLR7 antagonist HCQ治療後其表現IL-17和IFN-γ之免疫細胞族群 76
圖二十 分析經過TLR7 antagonist HCQ治療後tEAU小鼠其脾臟細胞之調控型T細胞族群 78
圖二十一 分析經過HCQ治療後tEAU小鼠其脾臟細胞經IRBP刺激後分泌之IL-17和IFN-γ 79
圖二十二 分析經過HCQ治療後tEAU小鼠其RPE細胞TLR7之基因表現量 80
圖二十三 檢測pRPE在in vitro環境下經過R848刺激後所分泌之IL-6 81
圖二十四 檢測pRPE在in vitro環境下經過HCQ刺激後所分泌之IL-6 82

 
附錄目錄
附錄一 小鼠葡萄膜炎疾病評分方式 83
附錄二 小鼠葡萄膜炎眼底發炎程度評估實例 84
附錄三 本論文中所用之即時定量PCR引子表 85
附錄四 評估給予TLR7 agonist R848對IL-17KO小鼠其tEAU疾病進程之影響 86
附錄五 分析給予TLR7 agonist R848後IL-17KO之tEAU小鼠其表現IFN-γ免疫細胞之族群 88
附錄六 分析給予TLR7 agonist R848後IL-17KO之tEAU小鼠其脾臟細胞之調控型T細胞族群 89
附錄七 分析給予TLR7 agonist R848後IL-17KO之tEAU小鼠其經IRBP刺激後脾臟細胞分泌之IFN-γ 90
附錄八 分析給予TLR7 agonist R848後IL-17KO之tEAU小鼠其RPE細胞TLR7之基因表現 91
附錄九 小鼠RPE細胞的TLR7訊息傳遞參與tEAU之疾病發展 92

Agarwal, R. K., Silver, P. B., &; Caspi, R. R. (2012). Rodent models of experimental autoimmune uveitis. Methods Mol Biol, 900, 443-469.
Agarwal, R. K., Sun, S. H., Su, S. B., Chan, C. C., &; Caspi, R. R. (2002). Pertussis toxin alters the innate and the adaptive immune responses in a pertussis-dependent model of autoimmunity. J Neuroimmunol, 129(1-2), 133-140.
Allensworth, J. J., Planck, S. R., Rosenbaum, J. T., &; Rosenzweig, H. L. (2011). Investigation of the differential potentials of TLR agonists to elicit uveitis in mice. J Leukoc Biol, 90(6), 1159-1166.
Avichezer, D., Liou, G. I., Chan, C. C., Lewis, G. M., Wiggert, B., Donoso, L. A., . . . Caspi, R. R. (2003). Interphotoreceptor retinoid-binding protein (IRBP)-deficient C57BL/6 mice have enhanced immunological and immunopathogenic responses to IRBP and an altered recognition of IRBP epitopes. J Autoimmun, 21(3), 185-194.
Bainbridge, J. W., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., . . . Ali, R. R. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med, 358(21), 2231-2239.
Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., . . . Kuchroo, V. K. (2006). Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441(7090), 235-238.
Bihl, F., Lariviere, L., Qureshi, S. T., Flaherty, L., &; Malo, D. (2001). LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4. Genes Immun, 2(1), 56-59.
Bok, D. (1993). The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl, 17, 189-195.
Bsibsi, M., Persoon-Deen, C., Verwer, R. W., Meeuwsen, S., Ravid, R., &; Van Noort, J. M. (2006). Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia, 53(7), 688-695.
Cai, J., Nelson, K. C., Wu, M., Sternberg, P., Jr., &; Jones, D. P. (2000). Oxidative damage and protection of the RPE. Prog Retin Eye Res, 19(2), 205-221.
Calder, V. L., &; Lightman, S. L. (1992). Experimental autoimmune uveoretinitis (EAU) versus experimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms. Clin Exp Immunol, 89(2), 165-169.
Caspi, R. R. (2002). Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis. Int Rev Immunol, 21(2-3), 197-208.
Caspi, R. R. (2010). A look at autoimmunity and inflammation in the eye. J Clin Invest, 120(9), 3073-3083.
Caspi, R. R., Chan, C. C., Grubbs, B. G., Silver, P. B., Wiggert, B., Parsa, C. F., . . . Heremans, H. (1994). Endogenous systemic IFN-gamma has a protective role against ocular autoimmunity in mice. J Immunol, 152(2), 890-899.
Caspi, R. R., Roberge, F. G., Chan, C. C., Wiggert, B., Chader, G. J., Rozenszajn, L. A., . . . Nussenblatt, R. B. (1988). A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J Immunol, 140(5), 1490-1495.
Caspi, R. R., Roberge, F. G., McAllister, C. G., el-Saied, M., Kuwabara, T., Gery, I., . . . Nussenblatt, R. B. (1986). T cell lines mediating experimental autoimmune uveoretinitis (EAU) in the rat. J Immunol, 136(3), 928-933.
Chan, C. C., Caspi, R. R., Ni, M., Leake, W. C., Wiggert, B., Chader, G. J., &; Nussenblatt, R. B. (1990). Pathology of experimental autoimmune uveoretinitis in mice. J Autoimmun, 3(3), 247-255.
Chan, C. C., Detrick, B., Nussenblatt, R. B., Palestine, A. G., Fujikawa, L. S., &; Hooks, J. J. (1986). HLA-DR antigens on retinal pigment epithelial cells from patients with uveitis. Arch Ophthalmol, 104(5), 725-729.
Chan, C. C., Mochizuki, M., Nussenblatt, R. B., Palestine, A. G., McAllister, C., Gery, I., &; BenEzra, D. (1985). T-lymphocyte subsets in experimental autoimmune uveitis. Clin Immunol Immunopathol, 35(1), 103-110.
Chang, C. W., Roque, R. S., Defoe, D. M., &; Caldwell, R. B. (1991). An improved method for isolation and culture of pigment epithelial cells from rat retina. Curr Eye Res, 10(11), 1081-1086.
Chen, L., Yang, P., Zhou, H., He, H., Ren, X., Chi, W., . . . Kijlstra, A. (2008). Diminished frequency and function of CD4+CD25high regulatory T cells associated with active uveitis in Vogt-Koyanagi-Harada syndrome. Invest Ophthalmol Vis Sci, 49(8), 3475-3482.
Chen, S., Yan, H., Sun, B., Zuo, A., &; Liang, D. (2013). Subretinal transfection of chitosan-loaded TLR3-siRNA for the treatment of experimental autoimmune uveitis. Eur J Pharm Biopharm, 85(3 Pt A), 726-735.
Chen, Y., Kijlstra, A., Chen, Y., &; Yang, P. (2011). IL-17A stimulates the production of inflammatory mediators via Erk1/2, p38 MAPK, PI3K/Akt, and NF-kappaB pathways in ARPE-19 cells. Mol Vis, 17, 3072-3077.
Detrick, B., &; Hooks, J. J. (2010). Immune regulation in the retina. Immunol Res, 47(1-3), 153-161.
Detrick, B., Lee, M. T., Chin, M. S., Hooper, L. C., Chan, C. C., &; Hooks, J. J. (2008). Experimental coronavirus retinopathy (ECOR): retinal degeneration susceptible mice have an augmented interferon and chemokine (CXCL9, CXCL10) response early after virus infection. J Neuroimmunol, 193(1-2), 28-37.
Detrick, B., Newsome, D. A., Percopo, C. M., &; Hooks, J. J. (1985). Class II antigen expression and gamma interferon modulation of monocytes and retinal pigment epithelial cells from patients with retinitis pigmentosa. Clin Immunol Immunopathol, 36(2), 201-211.
Detrick, B., Rodrigues, M., Chan, C. C., Tso, M. O., &; Hooks, J. J. (1986). Expression of HLA-DR antigen on retinal pigment epithelial cells in retinitis pigmentosa. Am J Ophthalmol, 101(5), 584-590.
Dominguez-Villar, M., Gautron, A. S., de Marcken, M., Keller, M. J., &; Hafler, D. A. (2015). TLR7 induces anergy in human CD4(+) T cells. Nat Immunol, 16(1), 118-128.
Elner, S. G., Petty, H. R., Elner, V. M., Yoshida, A., Bian, Z. M., Yang, D., &; Kindzelskii, A. L. (2005). TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression. Invest Ophthalmol Vis Sci, 46(12), 4627-4633.
Fang, J., Fang, D., Silver, P. B., Wen, F., Li, B., Ren, X., . . . Su, S. B. (2010). The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model. Invest Ophthalmol Vis Sci, 51(6), 3092-3099.
Forrester, J. V., Xu, H., Lambe, T., &; Cornall, R. (2008). Immune privilege or privileged immunity? Mucosal Immunol, 1(5), 372-381.
Fujino, Y., Okumura, A., Nussenblatt, R. B., Gery, I., &; Mochizuki, M. (1988). Cyclosporine-induced specific unresponsiveness to retinal soluble antigen in experimental autoimmune uveoretinitis. Clin Immunol Immunopathol, 46(2), 234-248.
Gibbs, D., &; Williams, D. S. (2003). Isolation and culture of primary mouse retinal pigmented epithelial cells. Adv Exp Med Biol, 533, 347-352.
Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R., &; Ferguson, T. A. (1995). Fas ligand-induced apoptosis as a mechanism of immune privilege. Science, 270(5239), 1189-1192.
Gritz, D. C., &; Wong, I. G. (2004). Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology, 111(3), 491-500; discussion 500.
Hamel, C. P., Tsilou, E., Pfeffer, B. A., Hooks, J. J., Detrick, B., &; Redmond, T. M. (1993). Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. J Biol Chem, 268(21), 15751-15757.
Holtkamp, G. M., Kijlstra, A., Peek, R., &; de Vos, A. F. (2001). Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retin Eye Res, 20(1), 29-48.
Hooks, J. J., Moutsopoulos, H. M., Geis, S. A., Stahl, N. I., Decker, J. L., &; Notkins, A. L. (1979). Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med, 301(1), 5-8.
Hooks, J. J., Nagineni, C. N., Hooper, L. C., Hayashi, K., &; Detrick, B. (2008). IFN-beta provides immuno-protection in the retina by inhibiting ICAM-1 and CXCL9 in retinal pigment epithelial cells. J Immunol, 180(6), 3789-3796.
Horai, R., &; Caspi, R. R. (2011). Cytokines in autoimmune uveitis. J Interferon Cytokine Res, 31(10), 733-744.
Jones, L. S., Rizzo, L. V., Agarwal, R. K., Tarrant, T. K., Chan, C. C., Wiggert, B., &; Caspi, R. R. (1997). IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response. J Immunol, 158(12), 5997-6005.
Kawashima, H., &; Mochizuki, M. (1990). Effects of a new immunosuppressive agent, FK 506, on the efferent limb of the immune responses. Exp Eye Res, 51(5), 565-572.
Ke, Y., Liu, K., Huang, G. Q., Cui, Y., Kaplan, H. J., Shao, H., &; Sun, D. (2009). Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol, 182(5), 3183-3190.
Ke, Y., Sun, D., Jiang, G., Kaplan, H. J., &; Shao, H. (2010). PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. J Leukoc Biol, 88(6), 1241-1249.
Kim, S. J., Zhang, M., Vistica, B. P., Chan, C. C., Shen, D. F., Wawrousek, E. F., &; Gery, I. (2002). Induction of ocular inflammation by T-helper lymphocytes type 2. Invest Ophthalmol Vis Sci, 43(3), 758-765.
Kindzelskii, A. L., Elner, V. M., Elner, S. G., Yang, D., Hughes, B. A., &; Petty, H. R. (2004). Toll-like receptor 4 (TLR4) of retinal pigment epithelial cells participates in transmembrane signaling in response to photoreceptor outer segments. J Gen Physiol, 124(2), 139-149.
Kleinman, M. E., Kaneko, H., Cho, W. G., Dridi, S., Fowler, B. J., Blandford, A. D., . . . Ambati, J. (2012). Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Mol Ther, 20(1), 101-108.
Kumar, M. V., Nagineni, C. N., Chin, M. S., Hooks, J. J., &; Detrick, B. (2004). Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol, 153(1-2), 7-15.
Kuznik, A., Bencina, M., Svajger, U., Jeras, M., Rozman, B., &; Jerala, R. (2011). Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol, 186(8), 4794-4804.
Lalive, P. H., Benkhoucha, M., Tran, N. L., Kreutzfeldt, M., Merkler, D., &; Santiago-Raber, M. L. (2014). TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+ Treg cells. Eur J Immunol, 44(1), 46-57.
Lamagna, C., Scapini, P., van Ziffle, J. A., DeFranco, A. L., &; Lowell, C. A. (2013). Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc Natl Acad Sci U S A, 110(35), E3311-3320.
Liversidge, J. M., Sewell, H. F., &; Forrester, J. V. (1988). Human retinal pigment epithelial cells differentially express MHC class II (HLA, DP, DR and DQ) antigens in response to in vitro stimulation with lymphokine or purified IFN-gamma. Clin Exp Immunol, 73(3), 489-494.
Macfarlane, D. E., &; Manzel, L. (1998). Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol, 160(3), 1122-1131.
Medawar, P. B. (1948). Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol, 29(1), 58-69.
Nagineni, C. N., Detrick, B., &; Hooks, J. J. (2000). Toxoplasma gondii infection induces gene expression and secretion of interleukin 1 (IL-1), IL-6, granulocyte-macrophage colony-stimulating factor, and intercellular adhesion molecule 1 by human retinal pigment epithelial cells. Infect Immun, 68(1), 407-410.
Nagineni, C. N., Samuel, W., Nagineni, S., Pardhasaradhi, K., Wiggert, B., Detrick, B., &; Hooks, J. J. (2003). Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol, 197(3), 453-462.
O'Neill, L. A., Bryant, C. E., &; Doyle, S. L. (2009). Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev, 61(2), 177-197.
Palsson-McDermott, E. M., &; O'Neill, L. A. (2004). Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology, 113(2), 153-162.
Patel, A. K., &; Hackam, A. S. (2013). Toll-like receptor 3 (TLR3) protects retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism. Mol Immunol, 54(2), 122-131.
Peng, Y., Han, G., Shao, H., Wang, Y., Kaplan, H. J., &; Sun, D. (2007). Characterization of IL-17+ interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci, 48(9), 4153-4161.
Percopo, C. M., Hooks, J. J., Shinohara, T., Caspi, R., &; Detrick, B. (1990). Cytokine-mediated activation of a neuronal retinal resident cell provokes antigen presentation. J Immunol, 145(12), 4101-4107.
Reiling, N., Holscher, C., Fehrenbach, A., Kroger, S., Kirschning, C. J., Goyert, S., &; Ehlers, S. (2002). Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol, 169(7), 3480-3484.
Ren, X., Zhou, H., Li, B., &; Su, S. B. (2011). Toll-like receptor 3 ligand polyinosinic:polycytidylic acid enhances autoimmune disease in a retinal autoimmunity model. Int Immunopharmacol, 11(6), 769-773.
Rizzo, L. V., Silver, P., Wiggert, B., Hakim, F., Gazzinelli, R. T., Chan, C. C., &; Caspi, R. R. (1996). Establishment and characterization of a murine CD4+ T cell line and clone that induce experimental autoimmune uveoretinitis in B10.A mice. J Immunol, 156(4), 1654-1660.
Samardzija, M., Wenzel, A., Naash, M., Reme, C. E., &; Grimm, C. (2006). Rpe65 as a modifier gene for inherited retinal degeneration. Eur J Neurosci, 23(4), 1028-1034.
Saraswathy, S., Nguyen, A. M., &; Rao, N. A. (2010). The role of TLR4 in photoreceptor {alpha}a crystallin upregulation during early experimental autoimmune uveitis. Invest Ophthalmol Vis Sci, 51(7), 3680-3686.
Schjetne, K. W., Thompson, K. M., Nilsen, N., Flo, T. H., Fleckenstein, B., Iversen, J. G., . . . Bogen, B. (2003). Cutting edge: link between innate and adaptive immunity: Toll-like receptor 2 internalizes antigen for presentation to CD4+ T cells and could be an efficient vaccine target. J Immunol, 171(1), 32-36.
Schuster, J. M., &; Nelson, P. S. (2000). Toll receptors: an expanding role in our understanding of human disease. J Leukoc Biol, 67(6), 767-773.
Segal, B. M., Chang, J. T., &; Shevach, E. M. (2000). CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol, 164(11), 5683-5688.
Shao, H., Liao, T., Ke, Y., Shi, H., Kaplan, H. J., &; Sun, D. (2006). Severe chronic experimental autoimmune uveitis (EAU) of the C57BL/6 mouse induced by adoptive transfer of IRBP1-20-specific T cells. Exp Eye Res, 82(2), 323-331.
Shao, H., Sun, S. L., Kaplan, H. J., &; Sun, D. (2004). Characterization of rat CD8+ uveitogenic T cells specific for interphotoreceptor retinal-binding protein 1177-1191. J Immunol, 173(4), 2849-2854.
Stein-Streilein, J., &; Taylor, A. W. (2007). An eye's view of T regulatory cells. J Leukoc Biol, 81(3), 593-598.
Streilein, J. W. (1999). Regional immunity and ocular immune privilege. Chem Immunol, 73, 11-38.
Streilein, J. W. (2003a). Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol, 74(2), 179-185.
Streilein, J. W. (2003b). Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nature Reviews Immunology, 3(11), 879-889.
Su, S. B., Silver, P. B., Grajewski, R. S., Agarwal, R. K., Tang, J., Chan, C. C., &; Caspi, R. R. (2005). Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol, 175(10), 6303-6310.
Sugita, S. (2009). Role of ocular pigment epithelial cells in immune privilege. Arch Immunol Ther Exp (Warsz), 57(4), 263-268.
Sugita, S., Kawazoe, Y., Imai, A., Usui, Y., Takahashi, M., &; Mochizuki, M. (2013). Suppression of IL-22-producing T helper 22 cells by RPE cells via PD-L1/PD-1 interactions. Invest Ophthalmol Vis Sci, 54(10), 6926-6933.
Sugita, S., &; Streilein, J. W. (2003). Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J Exp Med, 198(1), 161-171.
Sun, D., Enzmann, V., Lei, S., Sun, S. L., Kaplan, H. J., &; Shao, H. (2003). Retinal pigment epithelial cells activate uveitogenic T cells when they express high levels of MHC class II molecules, but inhibit T cell activation when they express restricted levels. J Neuroimmunol, 144(1-2), 1-8.
Sun, D., Whitaker, J. N., Huang, Z., Liu, D., Coleclough, C., Wekerle, H., &; Raine, C. S. (2001). Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol, 166(12), 7579-7587.
Sun, D., Zhang, Y., Wei, B., Peiper, S. C., Shao, H., &; Kaplan, H. J. (2003). Encephalitogenic activity of truncated myelin oligodendrocyte glycoprotein (MOG) peptides and their recognition by CD8+ MOG-specific T cells on oligomeric MHC class I molecules. Int Immunol, 15(2), 261-268.
Sun, S., Rao, N. L., Venable, J., Thurmond, R., &; Karlsson, L. (2007). TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets, 6(4), 223-235.
Takeda, K., &; Akira, S. (2004). TLR signaling pathways. Semin Immunol, 16(1), 3-9.
Tang, J., Zhu, W., Silver, P. B., Su, S. B., Chan, C. C., &; Caspi, R. R. (2007). Autoimmune uveitis elicited with antigen-pulsed dendritic cells has a distinct clinical signature and is driven by unique effector mechanisms: initial encounter with autoantigen defines disease phenotype. J Immunol, 178(9), 5578-5587.
Tian, L., Lei, B., Shao, J., Wei, L., Kijlstra, A., &; Yang, P. (2012). AAV2-mediated combined subretinal delivery of IFN-alpha and IL-4 reduces the severity of experimental autoimmune uveoretinitis. PLoS One, 7(6), e37995.
Touil, T., Fitzgerald, D., Zhang, G. X., Rostami, A., &; Gran, B. (2006). Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol, 177(11), 7505-7509.
Vallois, D., Grimm, C. H., Avner, P., Boitard, C., &; Rogner, U. C. (2007). The type 1 diabetes locus Idd6 controls TLR1 expression. J Immunol, 179(6), 3896-3903.
Wang, Z. Y., Yang, D., Chen, Q., Leifer, C. A., Segal, D. M., Su, S. B., . . . Oppenheim, J. J. (2006). Induction of dendritic cell maturation by pertussis toxin and its B subunit differentially initiate Toll-like receptor 4-dependent signal transduction pathways. Exp Hematol, 34(8), 1115-1124.
Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S., &; Cao, Z. (1997). MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity, 7(6), 837-847.
Xin-Zhao Wang, C., Zhang, K., Aredo, B., Lu, H., &; Ufret-Vincenty, R. L. (2012). Novel method for the rapid isolation of RPE cells specifically for RNA extraction and analysis. Exp Eye Res, 102, 1-9.
Xu, H., Rizzo, L. V., Silver, P. B., &; Caspi, R. R. (1997). Uveitogenicity is associated with a Th1-like lymphokine profile: cytokine-dependent modulation of early and committed effector T cells in experimental autoimmune uveitis. Cell Immunol, 178(1), 69-78.
Yang, Q., Wang, B., Yu, H., Zhu, Y., Wang, X., Jiang, H., . . . Hou, M. (2011). TLR7 promotes Th1 polarization in immune thrombocytopenia. Thromb Res, 128(3), 237-242.
Yoshimura, T., Sonoda, K. H., Miyazaki, Y., Iwakura, Y., Ishibashi, T., Yoshimura, A., &; Yoshida, H. (2008). Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis. Int Immunol, 20(2), 209-214.
Yu, C. F., Peng, W. M., Oldenburg, J., Hoch, J., Bieber, T., Limmer, A., . . . Novak, N. (2010). Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation. J Immunol, 184(3), 1159-1167.
Zhu, F. G., Jiang, W., Bhagat, L., Wang, D., Yu, D., Tang, J. X., . . . Agrawal, S. (2013). A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. Autoimmunity, 46(7), 419-428.
洪薇馨. (2015). 長庚大學醫學生物技術暨檢驗學系碩士班論文.