脊椎關節病變 (Spondyloarthropathy, SpA) 與HLA-B27關係密切。文獻及我們的研究已証實 HLA-B27分子可以以不完整的Tertiary structure-自由重鏈表現在細胞表面，這讓我們又理由相信“未折疊蛋白質反應” (Unfolded protein response) 可能是此類疾病致病的主要機轉之一。未折疊蛋白質反應為細胞內質網針對一些未折疊或折疊不完全的蛋白所誘發出來的一系列反應，它包括Chaperon-Bip 的大量形成、大量蛋白質的製造被壓抑以及將未折疊或折疊不好的蛋白質後送回細胞質加以摧毀代謝。因此“未折疊蛋白質反應”可以說是細胞中內質網對蛋白質形成的一套品質管控措施。我們的過去實驗已証實於SpA病人HLA(MHC) class Ι 分子被後送回細胞質中。於這個研究裏我們將進一步去評量SpA病人細胞中Chaperon Bip及其他HLA class 1相關的chaperon calnexin 和calreticulin表現的情形，並發現這3種和HLA class 1相關的chaperon在病人血球上的表現高於正常人及類風濕性關節炎病人。 期能為脊椎關節病變的致病機轉上展開一個完全嶄新的里程碑。

HLA-B27 is known to be highly correlated with spondyloarthropathies. Revious studies have confirmed that HLA-B27 is an unstable tertiary structurewith free heavy chain expressed on the cell surface. The authors were convinced that unfolded protein response (UPR) may be one of the main pathways in pathogenesis. UPR is a special way the endoplasmic reticulum use UPR to tightly control the quality of the protein to be transported, and this is induced by the presence of unfolded or incomplete folded proteins in the endoplasmic reticulum. The response included: the up-regulation of chaperon – Bip, the suppression of massive protein production by the phosphorylation of transcription initiation factors, and the back transport of the unfolded protein into cytoplasm for degradation. In a previous study, we revealed the back transport of HLA class I into the cytoplasm in cells of spondyloarthropathies patients. In this study, I focus on the expression of the chaperon – Binding immunoglobulin protein (Bip), calnexin and clareticulin by the quantitative PCR on the cells in patients with spondyloarthropathies to verify the importance of unfolded protein response as one of the key factors in the pathogenesis of these diseases.

目 錄
論文審定書…………………………………………………………………………………………… i
誌謝………………………………………………………………...…………………………………… ii
中文摘要……………………………………………………..……………………………….…….. iii
英文摘要……………………………………………………..……………..………………………. iv
第 一 章 前言……………………………………….……………………………......… 1-4
第 二 章 材料方法……………………………………………………………………… 5-6
第 三 章 結果……………………………………………………………………………… 7-8
第 四 章 討論……………………………………………………………………………… 9-11
參考文獻…………………………………………………………12-14

Allen, R. L., O'Callaghan, C. A., McMichael, A. J., & Bowness, P. (1999). Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol, 162(9), 5045-5048.

Andersen, T. B., Lopez, C. Q., Manczak, T., Martinez, K., & Simonsen, H. T. (2015). Thapsigargin--from Thapsia L. to mipsagargin. Molecules, 20(4), 6113-6127. doi:10.3390/molecules20046113

Barnea, E., Melamed Kadosh, D., Haimovich, Y., Satumtira, N., Dorris, M. L., Nguyen, M. T., . . . Admon, A. (2017). The Human Leukocyte Antigen (HLA)-B27 Peptidome in Vivo, in Spondyloarthritis-susceptible HLA-B27 Transgenic Rats and the Effect of Erap1 Deletion. Mol Cell Proteomics, 16(4), 642-662. doi:10.1074/mcp.M116.066241

Cauli, A., Piga, M., Dessole, G., Porru, G., Floris, A., Vacca, A., . . . Mathieu, A. (2014). Killer-cell immunoglobulin-like receptors (KIR) and HLA-class I heavy chains in ankylosing spondylitis. Drug Dev Res, 75 Suppl 1, S15-19. doi:10.1002/ddr.21187

Cobbold, C., Monaco, A. P., Sivaprasadarao, A., & Ponnambalam, S. (2003). Aberrant trafficking of transmembrane proteins in human disease. Trends Cell Biol, 13(12), 639-647. doi:10.1016/j.tcb.2003.10.008

Colbert, R. A., Navid, F., & Gill, T. (2017). The role of HLA-B*27 in spondyloarthritis. Best Pract Res Clin Rheumatol, 31(6), 797-815. doi:10.1016/j.berh.2018.07.012

Dangoria, N. S., DeLay, M. L., Kingsbury, D. J., Mear, J. P., Uchanska-Ziegler, B., Ziegler, A., & Colbert, R. A. (2002). HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem, 277(26), 23459-23468. doi:10.1074/jbc.M110336200

David, C. S. (1997). The mystery of HLA-B27 and disease. Immunogenetics, 46(1), 73-77. doi:10.1007/s002510050244

Gras, S., Burrows, S. R., Turner, S. J., Sewell, A. K., McCluskey, J., & Rossjohn, J. (2012). A structural voyage toward an understanding of the MHC-I-restricted immune response: lessons learned and much to be learned. Immunol Rev, 250(1), 61-81. doi:10.1111/j.1600-065X.2012.01159.x

Jackson, C. L., & Miller, E. A. (2015). Protein sorting to intracellular compartments. Mol Biol Cell, 26(6), 1014. doi:10.1091/mbc.E14-12-1595

Kaslow, R. A., Ryder, R. W., & Calin, A. (1979). Search for Reiter's syndrome after an outbreak of Shigella sonnei dysentery. J Rheumatol, 6(5), 562-566.

Khan, M. A. (1996). Epidemiology of HLA-B27 and Arthritis. Clin Rheumatol, 15 Suppl 1, 10-12. doi:10.1007/BF03342637

Liu, C. H., Raj, S., Chen, C. H., Hung, K. H., Chou, C. T., Chen, I. H., . . . Lin, K. I. (2019). HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J Clin Invest, 129(12), 5357-5373. doi:10.1172/JCI125212

Liu, C. Y., & Kaufman, R. J. (2003). The unfolded protein response. J Cell Sci, 116(Pt 10), 1861-1862. doi:10.1242/jcs.00408

Madden, D. R., Gorga, J. C., Strominger, J. L., & Wiley, D. C. (1992). The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell, 70(6), 1035-1048. doi:10.1016/0092-8674(92)90252-8

Mear, J. P., Schreiber, K. L., Munz, C., Zhu, X., Stevanovic, S., Rammensee, H. G., . . . Colbert, R. A. (1999). Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol, 163(12), 6665-6670.

Neefjes, J., Jongsma, M. L., Paul, P., & Bakke, O. (2011). Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol, 11(12), 823-836. doi:10.1038/nri3084

Preissler, S., & Ron, D. (2019). Early Events in the Endoplasmic Reticulum Unfolded Protein Response. Cold Spring Harb Perspect Biol, 11(4). doi:10.1101/cshperspect.a033894

Saunders, P. M., & van Endert, P. (2011). Running the gauntlet: from peptide generation to antigen presentation by MHC class I. Tissue Antigens, 78(3), 161-170. doi:10.1111/j.1399-0039.2011.01735.x

Schubert, U., Anton, L. C., Gibbs, J., Norbury, C. C., Yewdell, J. W., & Bennink, J. R. (2000). Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature, 404(6779), 770-774. doi:10.1038/35008096

Tedeschi, V., Alba, J., Paladini, F., Paroli, M., Cauli, A., Mathieu, A., . . . Fiorillo, M. T. (2019). Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation. Cells, 8(6). doi:10.3390/cells8060572

Tsai, W. C., Chen, C. J., Yen, J. H., Ou, T. T., Tsai, J. J., Liu, C. S., & Liu, H. W. (2002). Free HLA class I heavy chain-carrying monocytes--a potential role in the pathogenesis of spondyloarthropathies. J Rheumatol, 29(5), 966-972.

Turner, M. J., & Colbert, R. A. (2002). HLA-B27 and pathogenesis of spondyloarthropathies. Curr Opin Rheumatol, 14(4), 367-372. doi:10.1097/00002281-200207000-00006

van Deutekom, H. W., & Kesmir, C. (2015). Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most? Immunogenetics, 67(8), 425-436. doi:10.1007/s00251-015-0849-y

Wordsworth, P. (1995). Genes and arthritis. Br Med Bull, 51(2), 249-266. doi:10.1093/oxfordjournals.bmb.a072959

Yair-Sabag, S., Tedeschi, V., Vitulano, C., Barnea, E., Glaser, F., Melamed Kadosh, D., . . . Admon, A. (2018). The Peptide Repertoire of HLA-B27 may include Ligands with Lysine at P2 Anchor Position. Proteomics, 18(9), e1700249. doi:10.1002/pmic.201700249