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系統識別號 U0026-0812200914135226
論文名稱(中文) EB病毒第一型潛伏性膜蛋白在T細胞中促進甲型腫瘤壞死因子之 分子機轉及其在噬血症候群的意義
論文名稱(英文) Molecular Mechanism for the Upregulation of Tumor Necrosis Factor-alpha by Epstein-Barr Virus (EBV) Latent Membrane Protein-1 in T Cells: Implication for EBV-associated hemophagocytic syndrome
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 莊懷佳
研究生(英文) Huai-Chia Chuang
學號 s5893145
學位類別 博士
語文別 英文
論文頁數 123頁
口試委員 口試委員-賴明德
口試委員-黎煥耀
指導教授-蘇益仁
口試委員-黃立民
召集委員-劉校生
口試委員-洪文俊
口試委員-張仲明
口試委員-葉才明
中文關鍵字 噬血症候群  EB病毒第一型潛伏性膜蛋白 
英文關鍵字 EBV  hemophagocytic syndrome  LMP1 
學科別分類
中文摘要 EB病毒是一種廣泛感染人類的疹病毒,EB病毒主要感染B細胞,引起感染性單核白血球增多症 (infectious mononucleosis)。在少數病人,EB病毒會感染T淋巴細胞,並造成致命的噬血症候群 (hemophagocytic syndrome, HPS or hemophagocytic lymphohistiocytosis, HLH ),並可能發展成T細胞淋巴瘤。HPS是由於T細胞過度活化、增生,並分泌大量的Th1細胞激素IFN-與TNF所造成的全身組織傷害。之前的研究已證實, EB病毒的第一型潛伏性膜蛋白(latent membrane protein 1, LMP1)會活化T細胞並分泌TNF與IFN,當中的訊息傳遞機轉仍待釐清。本論文的目的即探討EB病毒感染T細胞,導致TNF過度活化並引起噬血症候群的分子機轉。在論文的第一部分主要探討EB病毒LMP1對SAP基因的調控。在年幼小兒有一種疾病X-lined lymphoproliferative disorder (XLP) 同樣會引發HPS,此病是由於病人X染色體上SAP基因突變所致,SAP是一負調控蛋白,可透過抑制SLAM/ERK訊息而避免T細胞過度活化。當SAP蛋白缺損或突變時,如有EB病毒感染,T細胞會持續活化,造成細胞激素持續分泌而引發HPS。本論文因此研究,LMP1在T細胞中是否透過調控SAP而誘發大量的細胞激素,進而導致HPS/HLH。我們的研究發現,LMP1 在T細胞中可以抑制SAP基因的轉錄,而造成SAP蛋白表現量降低。因此造成SLAM訊息路徑下游分子ERK磷酸化,並引發IFN- 及TNF-分泌。此外,藉由TRAF2,5的dominant negative質體與LMP1共同表現或是加入NFB抑制劑,我們證實LMP1是透過TRAF2,5及NFB的訊息傳遞而抑制SAP基因的轉錄。而在LMP1表現的T細胞中再過量表現SAP,可以回復SLAM訊息傳遞對T細胞活化的負調控。第一部分的研究顯示,LMP1 在T細胞中經由NFB活化而抑制SAP表現,促使T細胞活化以及分泌細胞激素,因而導致HPS/HLH,提供了HPS一個共通的分子致病機制。

然而,透過NFB活化而抑制SAP轉錄是十分特殊的機制,本論文第二部分接續研究其中的調控機轉。利用cDNA microarray篩選後發現,LMP1 表現可活化轉錄因子ATF5的表現。因此,NFB可能經由ATF5來抑制SAP的表現。為証明此一推論,我們將LMP1與ATF5 siRNA共同表現在 T細胞中,發現可降低ATF5表現量並使SAP的表現恢復。而如果過量表現ATF5則會抑制SAP表現並促使T細胞活化且IFN與TNF過度分泌。為了澄清其調控機制,我們再利用luciferase reporter assay偵測ATF5調控SAP promoter活性的部位,經以刪除突變法分析,定出SAP promoter序列上的-420~-210片段是LMP1透過ATF5抑制SAP表現的反應區域。此外,利用染色質免疫沉澱實驗(Chromatin IP)及膠體電泳位移分析(EMSA)方法更進一步證實,LMP1所調增的ATF5可直接與-420~-210以及-210~+11兩個部位結合。進一步以突變結合位置進一步偵測SAP promoter活性並與EMSA結果比對,發現ATF5與promoter位置的-305~ -296位置的親合力較低,須在高濃度的ATF5時才能結合,ATF5與-81~ -74部位的結合較高,在平常生理狀況的ATF5濃度下即可結合並啟動SAP的表現。當ATF5過度表現時,可能是ATF5形成雙聚體(dimer)或四聚體(tetramer),造成SAP promoter區域折疊(looping)而無法進行SAP的轉錄,或經由一轉錄輔助因子的連結,造成T細胞過度活化並分泌大量的細胞激素。此研究結果將有助於瞭解EB病毒相關噬血症候群的分子致病機轉。ATF5對SAP的調控作用也可在PHA刺激T細胞或以CD3/CD28結合T細胞活化下觀測到,因此在其他免疫相關的HPS也可能經由此一機制來引發。

由於有部分HPS病人在治療後會復發或演變為T細胞淋巴瘤,因此推論EB病毒感染的T細胞可能會逃避TNF的毒殺作用,而有存活或生長優勢,本論文的第三部分進一步研究LMP1對TNF/TNFR1/TRADD此一信息傳遞路徑的影響,來澄清LMP1表現的T細胞如何逃避TNF所誘發的細胞凋亡而產生淋巴瘤。我們的結果顯示,LMP1可降低TNF所誘發的T細胞細胞凋亡,並降低此訊息傳導下cytochrome C及Caspase 3/8/9的活性而降低細胞凋亡。我們也發現LMP1在T細胞中會抑制TNFR1表現,透過TRAF2,5的dominant negative 質體再進一步證明,LMP1是經由TRAF以抑制TNFR1,並且與原本負責中介TNFR訊息的TRADD分子持續地結合而抑制細胞凋亡。此外,利用去甲基化劑藥劑證明,LMP1可能是透過將TNFR1甲基化進而抑制TNFR1的表現。因此,EB病毒的LMP1不僅促使T細胞過度活化及分泌TNF,更可同時躲避TNF所誘發的細胞凋亡,使病毒感染的T細胞得以存活並進一步增生及癌化。

本論文的各項研究結論可以提供EB病毒感染T細胞引發HPS及T細胞淋巴瘤發生的分子機制,並可提供臨床上標靶治療噬血症候群及T細胞淋巴瘤的基礎。
英文摘要 Epstein-Barr virus (EBV) is a ubiquitous human herpes virus that once infects T cells, will result in fatal infectious mononucleosis or sporadic type hemophagocytic syndrome (HPS) and associate with development of T cell lymphoma. HPS is a systemic tissue injuries caused by a dysregulation in T cell activation, proliferation, and overt secretion of Th1 cytokine, such as IFN and TNF. EBV latent membrane protein-1 (LMP1) was previously documented to be the responsible antigen for inducing TNF secretion in T cells. The signaling of LMP1-mediated excessive cytokine secretion remains to be studied. This thesis is designed to clarify the molecular mechanism involving in the upregulation of TNF by EBV LMP1. In the first part of this thesis, the regulation of SAP gene by LMP1 is studied. In X-linked lymphoproliferative disorder (XLP), dysfunction or mutation of SAP gene is responsible for the overt T cell activation and results in HPS. Whether SAP gene regulation is involved in EBV HPS or childhood hemophagocytic lymphohistiocytosis (HLH) was investigated. Despite no mutation of SAP gene in patients with sporadic type HPS/HLH, the transcriptional expression of SAP was downregulated in LMP1-expressed T cells, resulting in the activation of downstream signal SLAM/ERK1/2 and enhanced TNF/INFsecretion. The LMP-1-induced inhibition of SAP expression was mediated through the adaptor proteins TRAF2/5 and NFB pathway. The first part data conclude that LMP1/NFB-mediated SAP suppression induced T cell activation and Th1 cytokine secretion, providing a common mechanism for HPS in XLP and sporadic type HPS/HLH.
The downregulation of SAP via active NFB to activate T cells, however, is a novel phenomenon, and the underlying mechanism need to be further clarified. In the second part of thesis, the transcriptional repressor ATF5 was identified as the potential candidate for NFB-promoted suppression of SAP by cDNA microarray. SAP expression was suppressed by LMP1 expression, ligand-engaging of T cell activation, or in vitro overexpression of ATF5 in T cells, and ATF5 siRNA could rescue the expression of SAP. Luciferase reporter assay revealed that ATF5 inhibited SAP transcription on the response region -420~ -210 of SAP promoter. Moreover, the ChIP assay and EMSA assay demonstrated that normal concentration of ATF5 bound with high affinity to site -81~ -74, and abundant ATF5 could further bind to the low affinity site -305~ -296. Mutation of either site failed to suppress SAP transcription. Therefore, ATF5 may dimerize or tetramerize with each other to form a loop of SAP promoter, subsequently disrupting the transcription of SAP gene. The results of this part study provide a potential mechanism for the overt T cell activation in EBV HPS/HLH and immune disorders associated with HPS such as systemic lupus erythematosus.
Although the EBV-infected or LMP1-expresed T cells will lead to fatal HPS, patients with HPS may relapse or progress to T cell lymphoma. The EBV-infected, LMP-1-expressed T cells may potentially evade from the cytokine-induced apoptosis and persist or proliferate to become chronic active diseases. Therefore, the sensitivity of LMP-1-expressed T cells to TNF was further studied. The LMP1-expressing T cells were relatively resistant to TNF-induced apoptosis, compared with control T cells. The DNA fragmentation, activities of caspase 3/8/9, and cytochrome C release were decreased in LMP1-expressing T cells, even with addition of exogenous TNF. Interestingly, the TNFR1 expression was downregulated by LMP-1 and the TRADD molecule was recruited by LMP1, thereby blocking the TNF/TNFR1-induced apoptosis. Reconstitution of TNFR1 successfully reversed the apoptotic cascades in LMP1-expressed T cells. This finding provides a mechanism to explain the chronic active disease or disease progression in patients with EBV HPS/HLH. The LMP1-mediated suppression of TNFR1 could be rescued by treating with demethyltransferase drug, suggesting that methylation plays a role in regulation of promoter by LMP-1. Therefore, EBV LMP1 not only activates T cells with overt secretion of Th1 cytokines, but also confers resistance to TNF-mediated apoptosis via methylating TNFR1 in HPS.
The results of this thesis provide molecular insight to clarify the pathogenesis of EBV-associated HPS/HLH in children. Therapeutic trial can be therefore designed to provide a comprehensive therapy for patients with this fatal disorder.
論文目次 Contents ------------------------------------- 1
Abstract in English --------------------------- 6
Abstract in Chinese ---------------------------- 8
1. Introduction ------------------------------- 10
1.1. Epstein-Barr Virus Structure and Genome ---- 10
1.2. EBV Infection ------------------------ 12
1.2.1. EBV antigens ------------------ 13
1.2.1.1. EBV antigens in lytic cycle 13
1.2.1.2. EBV antigens in latent cycle 14
1.3. EBV-associated diseases
1.3.1. Infectious mononucleosis (IM) ----------- 15
1.3.2. Chronic active EBV infection (CAEBV) ----- 16
1.3.3. Hodgkin disease ---------------------- 17
1.3.4. Burkitt’s lymphoma (BL) ---------------- 17
1.3.5. Lymphomas in immunodeficiency ----------- 18
1.3.6. T or NK cell lymphoma ------------------- 19
1.3.7. Naspharyngeal carcinoma (NPC) ----------- 20
1.3.8. Gastric cancer ------------------------- 21
1.4. Hemophagocytic syndrome (HPS) -------- 21
1.4.1. X-linked lymphoproliferative disorder --- 22
1.4.2. Familial hemophagocytic lymphohistiocytosi 23
1.4.3. Sporadic hemophagocytic lymphohistiocytosis 23
1.4.3.1. Disease progression to clonal T cell disease or T cell lymphoma -------------------------- 25
1.4.3.2. EBV infection of T cells induces cytokines secretion and macrophage activation ------ 25
1.4.3.3. LMP1 crucially contributes to TNFsecretion -------------------------------------------------- 26
1.5. LMP1 Signaling Pathway ------------------ 26
28
2. Materials and Methods
2.1. Materials -------------------------------- 31
2.2. Methods ---------------------------------- 35
2.2.1. Patients and tissue samples ----------- 35
2.2.2. Cell culture -------------------------- 35
2.2.3. Transfection of T cell lines by electropoeration for stable clones ----------------------------- 35
2.2.4. Retrovirus delivered SAP DNA to T cell -- 36
2.2.5. Purification of primary CD3+ T cells ----- 36
2.2.6. Transient transfection of T cell lines or primary T cells ---------------------------------------- 36
2.2.7. PCR amplification and Reverse-transcriptase PCR analysis -------------------------------------- 37
2.2.8. Extraction of cytoplasmic and nuclear proteins --------------------------------------------------- 37
2.2.9. Co-immunoprecipitation assay ---------- 37
2.2.10. Western blot ------------------------- 38
2.2.11. Immunofluorescence staining ---------- 38
2.2.12. NF-κB promoter reporter assays ------- 39
2.2.13. Enzyme-linked Immunosorbent Assay (ELISA)- 39
2.2.14. Microarray analysis ------------------ 39
2.2.15. SAP promoter reporter assay --------- 40
2.2.16. Chromatin Immunoprecipitation (ChIP) --- 40
2.2.17. Electrophoresis mobility shift assay (EMSA) ----------------------------------------------------- 40
2.2.18. Detection of apoptosis ---------------- 41
2.2.19. Cytotoxicity bioassay of TNFα secreted in the culture supernatant ----------------------------- 42
3. Results
3.1. The LMP1 transcriptionally suppressed SAP gene through TRAF/NFB pathway
3.1.1. No detectable mutations on exon 2/3 of SAP/SH2D1A gene in seven sporadic HLH patients ----------- 43
3.1.2. LMP1 suppressed the expression of SAP gene at the transcriptional level in T cell lines --------- 43
3.1.3. TRAF2/5 signals were involved in LMP1-mediated suppression of SAP gene on T cell lines ------- 44
3.1.4. Involvement of NF-B in LMP1-mediated suppression of SAP in H9 T cells--------------------------- 45
3.1.5. The SLAM downstream molecules ERK and IFN-were activated and induced by LMP1-mediated SAP suppression --------------------------------------------------- 45
3.1.6. Conclusion ----------------------------- 46
3.2. LMP1 upregulated ATF5 to suppress SAP transcription
3.2.1. ATF5, not ATF3/7, plays a key role in LMP1-induced suppression of SAP --------------------------- 46
3.2.2. Overexpression of ATF5 downregulates SAP and enhances cytokine secretion ------------------ 47
3.2.3. LMP1 upregulate ATF5 via TRAF2,5/NFB signal pathway -------------------------------------- 48
3.2.4. Activated primary T cells show upregulation of ATF5 and downregulation of SAP ------------------- 48
3.2.5. The region -420 ~ -210 of SAP promoter is responsible for inhibition of SAP expression by ATF5- 49
3.2.6. ATF5 exactly bound to regions -305~ -296 and -81~ -74 for suppressing SAP promoter activity ----- 50
3.3. LMP1 inhibits TNFR to escape TNF--induced apoptosis
3.3.1. EBV LMP-1 enhanced the production and secretion of TNFvia the TRAF2/TRAF5/NF-B signal pathway in T cells ------------------------------------------ 51
3.3.2. The LMP1-upregulated TNF was cytotoxic factor ---------------------------------------------------- 52
3.3.3. LMP1-expressed T cells were resistant to apoptosis induced by exogenous TNF ------------------ 53
3.3.4. Downregulation of p55 TNFR1 by LMP1 in T cell lines and in primary T cells -------------------- 54
3.3.5. Constitutive recruitment of TRADD by LMP1 in H9 T cells ------------------------------------------ 55
3.3.6. TRADD co-locolized with LMP1, but not with TNFR1, in T cells --------------------------------------- 55
3.3.7. Reconstitution of TNFR1 restored apoptosis in LMP1-expressed H9 T cells --------------------------- 56
3.3.8. The LMP1-mediated TNFR1 suppression could be reversed by demethylation drug ----------------- 57
4. Discussion ---------------------------------- 58
4.1. The LMP1-mediated signaling pathway in sporadic HLH
4.1.1. No detectable mutations on exon2/3 of the SAP gene in sporadic HLH -------------------------------- 58
4.1.2. LMP1 suppressed the expression of SAP gene in T cells and some B cells ------------------------- 59
4.1.3. LMP1 signaling transduction for SAP suppression in T cells ----------------------------------------- 59
4.1.4. The LMP1 suppresses of SAP gene through regulating SAP transcription ------------------------------- 60
4.1.5. The LMP1/TRAF/NFB signaling in HLH cross-talks with SLAM/SAP/ERK signaling in XLP -------------- 60
4.2. LMP1 suppresses SAP gene via ATF5 to activate T cells
4.2.1. Virus can regulate gene expression by transcriptional repressor ------------------------ 61
4.2.2. ATF5 is a transcriptional repressor responsible for SAP suppression --------------------------------- 61
4.2.3. ATF5 dually binds to two sites of SAP promoter with different affinity ------------------------------ 61
4.2.4. The potential mechanism of ATF5 for suppressing SAP --------------------------------------------- 63
4.2.5. The unconventional binding mechanism of ATF5 provides conditional regulation ---------------- 64
4.2.6. ATF5 plays a crucial role in T cell activation ------------------------------------------------------ 64
4.3. LMP1 inhibits TNFR1 expresssion and facilitates cell survival
4.3.1. LMP1 and TNFR1 signal determines the cell fate ------------------------------------------------------ 65
4.3.2. Viruses seem to escape from immune attack and facilitate tumorigenesis ----------------------- 67
4.3.3. LMP1 and other TNFR family members ------- 67
4.3.4. LMP1/NFB signal induces Th1 cytokines and initiate inflammatory-associated cancer --------- 68
4.3.5. Will JNK signaling play a role? ---------- 69
4.3.6. Inhibition of NFB provides a target therapy for HPS or lymphoma -------------------------------- 69
5. References ---------------------------------- 71
6. Tables
Table 1. --- ------------------------------------ 90
Table 2. ---------------------------------------- 91
Table 3. ---------------------------------------- 92
7. Figures
Figure 1. The EBV virus genomes ----------------- 93
Figure 2. Suppression of SAP expression by LMP1 in T cell lines ------------------------------------------- 94
Figure 3. Involvement of TRAF2/5 in LMP1-mediated suppression of SAP on H9 cells ---------------- 95
Figure 4. NF-B involvement in LMP1-mediated suppression of SAP gene ----------------------------------- 96
Figure 5. The SLAM downstream molecules ERK and IFN- were activated by LMP1-mediated SAP suppression --- 98
Figure 6. Schematic depiction of the cross talk between the SLAM/SAP/ERK signaling in XLP and the LMP1/TRAF/NFB pathway in HLH ------------------------------------- 100
Figure 7. ATF5, not ATF3/7, plays an important role in LMP1-mediated suppression of SAP ---------------- 101
Figure 8. Overexpression of ATF5 induced secretion of Th1 cytokines via TRAF/NFB ------------------------ 103
Figure 9. Activated primary T cells or engaged- T cell lines showed upregulation of ATF5 -------------- 104
Figure 10. The region -420 ~ -210 of SAP promoter was responsible for inhibition by ATF5 ------------ 108
Figure 11. ATF5 exactly binds to site -305~ -296 and site -81~ -74 for suppressing SAP promoter activity ------ 109
Figure 12. Schematic depiction of the potential mechanism for the suppression of SAP by LMP1-mediated ATF5 in T cells --------------------------------------------- 111
Figure 13. LMP1 upregulated TNFvia the TRAF2/5/NFB signal pathway ----------------------------------- 112
Figure 14. Resistance of LMP1-expressed T cells to TNF-induced apoptosis --------------------------------- 114
Figure 15. Suppression of TNFR1 expression by LMP1 signaling in T cell lines and primary T cells ------ 116
Figure 16. Constitutive recruitment of TRADD by LMP1 in H9 T cells ------------------------------------------- 117
Figure 17. Co-localization of TRADD with TNFR1 and LMP1 in H9 T cells ---------------------------------------- 118
Figure 18. Restoration of TNF-induced apoptosis by reconstituted TNFR1 in LMP1-expressed H9 T cells --- 119
Figure 19. The LMP1-mediated TNFR1 suppression could be reversed by demethylation drug ------------------ 120
Figure 20. Schematic depiction of the molecular mechanism for the progression from HPS to chronic active disease or T cell lymphoma in EBV-infected T cells ----------- 122
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