The Effects of Sulfasalazine and Endoplasmic Reticulum-Targeted Antigenic Peptides on The Formation of HLA-B27 Heavy ChainDimer, A Key Molecule in The Pathogenesis ofAnkylosing Spondylitis.
| Autor: | Hui-Chun Yu, 游惠君 |
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| Rok vydání: | 2012 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 102 Ankylosing spondylitis (AS) is strongly associated with the expression of human leukocyte antigen-B27 (HLA-B27). HLA-B27 heavy chain (HC) has a propensity to fold slowly resulting in the accumulation of misfolded HLA-B27 HC in the ER, triggering the unfolded protein response, and forming a homodimer, (B27-HC)2. Natural killer cells and T-helper 17 cells are then activated, contributing to the major pathogenic potentials of AS. Sulfasalazine (SSA) is a medicine used for treatment of patients with peripheral arthritis. However, the effects of SSA treatment on suppression of IL-23/IL-17 axis and formation of (B27-HC)2 in peripheral blood mononuclear cells (PBMC) from AS patients remained to be determined. In my thesis, I first examined whether SSA can reduce the formation of (B27-HC)2 and suppress the production of pro-inflammatory factors. I found that after treatment with SSA for four months, the levels of (B27-HC)2 on PBMCs were significantly reduced. Cytokines mRNA levels, including TNF-, IL-17A, IL17F and INF-γ, were also significantly down-regulated in PBMCs. However, IL-23 was only weakly reduced. In conclusion, SSA was capable of suppressing the formation of (B27-HC)2, but is unable to significantly reduce the production of IL-23 in AS patients. In addition, the HLA-B27 HC is an important target, and delivery of an HLA-B27-binding peptide to the ER capable of promoting HLA-B27 HC folding is a potential mechanism for AS therapy. In the second part of this thesis, I demonstrated that a His6-ubiquitin-tagged Tat-derived peptide (THU) can deliver an HLA-B27-binding peptide to the ER, promoting HLA-B27 HC folding. The THU-HLA-B27-binding peptide fusion protein crossed the cell membrane to the cytosol through the Tat-derived peptide. The HLA-B27-binding peptide was specifically cleaved from THU by cytosolic ubiquitin C-terminal hydrolases and subsequently transported into the ER by the transporter associated with antigen processing. This approach has a potential application in the development of peptide therapy for AS. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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