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研究生：	張孔昭 Chang, Kung-Chao
論文名稱：	Epstein-Barr病毒在何杰金氏淋巴瘤的致病角色 The Role of Epstein-Barr Virus in Pathogenesis of Hodgkin Lymphoma
指導教授：	蘇益仁 Su, Ih-Jen 黎煥耀 Lei, Huan-Yao
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	93
中文關鍵詞：	內質網壓力、EB病毒、A型循環酶、第一型潛伏膜蛋白、流行病學、何杰金氏淋巴瘤
外文關鍵詞：	Epstein-Barr virus, Hodgkin lymphoma, epidemiology, latent membraneprotein 1, endoplasmic reticulum stress, cyclin A
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何杰金氏淋巴瘤 (HL) 是一種重要的人類腫瘤，最早在1832年為英國病理學家湯姆士何杰金 (Thomas Hodgkin) 博士所提出，此後便命名為何杰金氏症距今已超過一百五十年。不同於其他的人類淋巴腫瘤其腫瘤細胞為淋巴瘤的主要成分，HL的腫瘤細胞稱為H/RS (Hodgkin/Reed-Sternberg) 細胞佔不到腫瘤體積的十分之一，背景中主要是發炎細胞。這種謎樣的RS細胞具有獨特的豐富細胞質、兩葉的細胞核以及顯著的嗜伊紅核仁，活像貓頭鷹的眼睛。
這種病毒包涵體樣的細胞型態困惑了病理醫師但也導致了後來HL與EB病毒(Epstein-Barr病毒) 有密切關係的發現。然而這種相關會因地區的不同而有不同的結果。因此，EB病毒在各個地區與HL之相關性有待澄清。本論文中第一部分的研究旨在釐清台灣與越南兒童的HL與EB病毒的關聯性，越南是EB病毒感染的盛行區。藉著比較兩個時期 (1982至1995，74個案例以及1996至2007，99個案例) 的HL的病理特徵，以及EB病毒的關聯性，我們發現台灣的HL約一半與EB病毒有關聯且常發生於老年人的非結節硬化型，在後一時期中結節硬化型的比例增加，混合細胞型的比例減少，在結節硬化型與淋巴球枯竭型的HL中EB病毒的陽性率顯著減少。這些情況顯示在過去十幾年來台灣HL的病理流行病學分布逐漸朝向類似歐美與日本的型態。有趣的是在越南兒童的HL案例中其與EB病毒的關聯性接近百分之百，包括結節淋巴球優勢型。此亞型在西方國家的HL案例中與EB病毒沒有關聯。EB病毒在越南兒童HL的高度關聯性和EB病毒的首度感染即感染性單核球增多症的病人平均年齡較早有關係，在越南的病人是5.3歲而在已開發國家是15至19歲。我們的研究顯示在EB病毒感染年齡較早的地區，所有的小兒HL包括各個亞型幾乎都和EB病毒有關，而台灣在過去二、三十年間經濟及環境的改善，HL與EB病毒之相關性逐漸減少，這意味著在HL的致病機轉中環境因素扮演一個重要角色。
在第二階段的研究中，我們旨在發掘HL中RS細胞獨特型態的病理機轉。因為內質網壓力曾被發現會導致A型循環酶 (cyclin A) 在細胞質的變異表現，這樣的cyclin A會和cdk2一起作用，引發中心體過度複製而造成細胞多核的現象。故我們意欲驗證是否cyclin A在細胞質的變異表現會和RS細胞的獨特型態有關。藉著免疫染色研究34例的HL，我們發現cyclin A這個細胞週期調控者在細胞質的變異表現和RS細胞的獨特型態有關而且在EB病毒陽性與陰性的HL中皆如此。在EB病毒陰性的HL細胞株的實驗中，EB病毒的第一型潛伏膜蛋白會加強cyclin A在細胞質的表現。因此，cyclin A在細胞質的變異表現和RS細胞的獨特型態有關是何氏瘤的普遍現象。這機轉可能經由第一型潛伏膜蛋白的訊息路徑或類似機轉來達成。我們也首度發現大部分的HL案例會表現內質網壓力的存活訊息(GRP78, XBP1)而非死亡訊息(CHOP, ASK1)，這種表現存在於HL的各個亞型以及EB病毒陽性與陰性的HL中且比例相當。在HL細胞株的實驗中，第一型潛伏膜蛋白會加強內質網壓力存活訊息的表現。雖然內質網壓力訊息的表現和腫瘤預後無關，它卻可能使HL細胞免於壓力導致的細胞凋亡。因此由內質網壓力中存活可能和HL的致病機轉有關。
本論文成功的完成了台灣與越南兒童的HL與EB病毒關聯性的流行病學研究，並且提出了一個理論或機轉來解釋HL其RS細胞獨特的病理型態。

Hodgkin lymphoma (HL) is one of the most important human malignancies. It has been recognized since 1832 by Dr. Thomas Hodgkin, an English pathologist, and thereafter referred to as Hodgkin “disease” for more than 150 years. In contrast to other human lymphomas, in which the tumor cells are the main populations of the tumor constituents, the tumor cells of HL, called “Hodgkin (H)/Reed-Sternberg (RS)” cells, account usually for less than 10% of tumor bulk against an inflammatory background. The enigmatic RS cells are unique in their abundant cytoplasm and characteristic bilobed nuclei with eosinophilic prominent nucleoli, imparting an “owl-eye” appearance.
The viral inclusion-like morphology puzzled pathologists and led to the finding of HL association with Epstein-Barr virus (EBV). The association of HL with EBV, however, is variable in different geographic regions. My thesis is therefore designed to explore the association of HL with EBV at different time period. Furthermore, the enigmatic pathogenesis of RS cells is investigated, especially its potential association with EBV. In my first period of study, we tried to clarify the EBV association with HL in Taiwan and Vietnam, a country popular for EBV infection. By comparing pathologic features and EBV status detected by in situ hybridization in 99 HL cases diagnosed between 1996-2007 with 74 HL diagnosed from 1982-1995, we found that EBV association rate in Taiwan HL was about 50% and more frequently found in old patients with non-nodular sclerosis type. There were an increased frequency of nodular sclerosis subtype, decreased frequency of the mixed cellularity subtype, and significant decrease in EBV positivity rates among the nodular sclerosis and lymphocyte depleted subtypes in the period of 1996-2007, as compared to that of 1982-1995, that is, there were shifts in the frequency of histologic subtype and EBV association of HL in Taiwan over the last decade, with a trend closer to that seen in Western countries and Japan. Interestingly, the association rate of EBV in Vietnamese childish HL cases is nearly 100%, including nodular lymphocyte-predominant (NLP) subtype, which always shows no association with EBV in Western HL cases. The high incidence of EBV in these cases of HL is correlated with an earlier mean age of presentation of primary EBV infection, i.e. infectious mononucleosis, at 5.3 years old, in this patient population, compared to an average of 15-19 years old reported in developed countries. Our study demonstrates that in an area with an earlier mean age of onset of EBV infection, nearly all cases of pediatric HL, including all histological patterns, may be related to EBV infection. It implies an important role for environmental factors in the pathogenesis of HL.
In the second stage of study, we tried to investigate the mechanism underlying the characteristic multinucleated RS cells. Since endoplasmic reticulum (ER) stress has been found to induce aberrant, cytoplasmic cyclin A expression, which will interact with Cdk2 to induce centrosome overduplication, leading to nuclear hyperdiploidy, we tested whether the aberrant expression of cyclin A is related to the RS morphology of HL cells. We found, by immunohistochemistry on 34 cases of HL, that aberrantly cytoplasmic expression of cyclin A, a cell cycle regulator, was associated with RS cell morphogenesis in both EBV-positive and -negative HL cases. In vitro, EBV-LMP1 induced cytoplasmic expression of cyclin A with an increase of multinucleated cell morphology in an EBV-negative HL cell line, L-428. Therefore, the aberrant expression of cyclin A is commonly associated with RS cell morphology in HL, probably through LMP1 signaling or other similar mechanisms in EBV-negative cases. We also demonstrate for the first time that the majority of HL cases expressed survival (GRP78 and XBP1) but not death (CHOP and ASK1) signals of endoplasmic reticulum (ER) stress in all histologic subtypes of HL and in both EBV-positive and –negative cases at a similar level. LMP1 transfection increased expression of GRP78 and XBP1 in L-428 cell line. Although, expression of ER signals did not bear prognostic significance, it may rescue HL cells from stress-induced cell death. Thus, surviving ER stress may be involved in the pathogenesis of HL.
My PhD study therefore successfully finished the epidemiology of the association of EBV with HL in Taiwan and in Vietnam, and proposed a theory or mechanism to explain the characteristic RS morphology of HL.

ABSTRACT IN CHINESE  ---------------------------------------------------------------  1  
ABSTRACT IN ENGLISH  ---------------------------------------------------------------  3
ACKNOWLEDGMENT  ------------------------------------------------------------------  5
CONTENTS  ---------------------------------------------------------------------------------  6
1. INTRODUCTION  ----------------------------------------------------------------------  10
    1.1. Hodgkin lymphoma  ------------------------------------------------------------  10
    1.2. Epstein-Barr virus and Hodgkin lymphoma  ------------------------------  11
    1.3. The oncogenic role of EBV-latent membrane protein 1  ----------------  12  
    1.4. Viral proteins, morphologic changes and cyclin A  -----------------------  13
    1.5. Viral proteins and endoplasmic reticulum stress  -------------------------  14
    1.6. Specific aims and study designs  ----------------------------------------------  16
2. MATERIALS AND METHODS  -----------------------------------------------------  17
    2.1. HL cases  --------------------------------------------------------------------------  17
      2.1.1. HL Cases in Taiwan  -------------------------------------------------------  17
    2.1.2. HL and IM cases in Vietnamese children  -----------------------------  17
    2.1.3. Study subjects for cyclin A in morphogenesis of HL cells  ---------  18
    2.1.4. HL Cases for ER stress expression  -------------------------------------  18
    2.2. Immunohistochemical staining  -----------------------------------------------  19
    2.3. EBV detection  --------------------------------------------------------------------  20
    2.4. Transfecting LMP1 into an HL Cell Line L-428  --------------------------  21
    2.5. Double immunofluorescence for LMP1 and cyclin A  --------------------  21
    2.6. Flow cytometric analysis  -------------------------------------------------------  22
    2.7. Immunoblotting assay  ----------------------------------------------------------  22
  2.8. Statistical analysis  ---------------------------------------------------------------  23
3. RESULTS  ---------------------------------------------------------------------------------  24
    3.1. Changing patterns of HL subtypes and EBV association in Taiwan  --  24
3.1.1. Relative frequency and clinicopathologic features  ------------------  24
3.1.2. The overall EBV positive rate was 50% in Taiwan HL from 1982 
to 2007  ------------------------------------------------------------------------  24
3.1.3. Shifts in the frequencies of HL subtype and EBV association from 
1982 to 2007  -----------------------------------------------------------------  25
    3.2. HL and EBV association in Vietnamese children  -------------------------  26
      3.2.1. Relative frequency and clinicopathologic features  ------------------  26
      3.2.2. EBV association present in all histologic subtypes of HL in Vietnam
           ------------------------------------------------------------------------------------  26
      3.2.3. Lower expression of B-cell markers in Vietnamese HL  ------------  27
      3.2.4. Earlier mean age for patients with infectious mononucleosis (IM) 
in Vietnam  -------------------------------------------------------------------  27
    3.3. Aberrant expression of cyclin A in HL cells  --------------------------------  28
      3.3.1. EBER and LMP1 expressions in HL  -----------------------------------  28
         3.3.1.1. Cytoplasmic expression of cyclin A associated with RS cell morphology  ----------------------------------------------------------  28
         3.3.1.2. Staining patterns of CD15, CD30 and CD99 not associated 
with HL cell morphology  ------------------------------------------  29
3.3.2. In vitro LMP1 expression increased multinucleated RS cell 
morphology in an HL cell line  -------------------------------------------  30
3.3.3. LMP1 increased cytoplasmic expression of cyclin A over time 
in L-428 cells  ----------------------------------------------------------------  30
    3.4. Expression of ER stress signals in HL  ---------------------------------------  31
      3.4.1. Relative frequency and clinicopathologic features  ------------------  31
           3.4.2. EBV positivity in 60% of all HL from northern and southern Taiwan
                -------------------------------------------------------------------------------------  31
           3.4.3. Expression of survival but not death signals of ER stress in the majority of HL cases  -------------------------------------------------------  31
    3.4.4. LMP1 transfection in L-428 line increased expression of GRP78 and XBP1  --------------------------------------------------------------------------  32
    3.4.5. Expression of ER stress signals not correlated with prognosis in HL patients  ------------------------------------------------------------------------  33
4. DISCUSSION  -----------------------------------------------------------------------------  34
    4.1. Changing patterns of HL subtypes and EBV association in Taiwan  ---  34 
4.1.1. Shifting from pattern 2 towards pattern 3 of HL in Taiwan with improved public health status  --------------------------------------------  34
4.1.2. HL may have different etiologies in different age groups and EBV positivity in HL is more frequently associated with the older age 
group  --------------------------------------------------------------------------  35
4.1.3. A dominant role for environmental factors in determining the type
 of HL  --------------------------------------------------------------------------  36
    4.2. HL and EBV association in Vietnamese children  -------------------------  36
      4.2.1. EBV association present in all histologic subtypes of HL  ----------  36
    4.2.2. Earlier exposure to EBV may be a predisposing factor for 
EBV-positive HL  ------------------------------------------------------------  37
      4.2.3. The oncogenic role of EBV in HL  ---------------------------------------  38
    4.3. Aberrant cytoplasmic expression of cyclin A in HL cells  ----------------  40
      4.3.1. Cytoplasmic expression of cyclin A is a common mechanism for the morphogenesis of RS cells in both EBV-positive and –negative HL 
cases  ---------------------------------------------------------------------------  40
      4.3.2. EBV-LMP1 signaling may be involved in the morphogenesis of RS 
cells in EBV-positive HL  ---------------------------------------------------  41
      4.3.3. The potential mechanisms underlying the cytoplasmic expression of 
cyclin A  ------------------------------------------------------------------------  41
      4.3.4. Cytoplasmic cyclin A expression and NFκB activation are common mechanisms in EBV-positive and -negative HL  -----------------------  42
    4.4. Expression of ER stress signals in HL  ----------------------------------------  43
      4.4.1. Expression of ER stress survival signals was universal in all histologic subtypes of HL and in both EBV-positive and –negative cases in a 
similar level  -------------------------------------------------------------------  43
      4.4.2. Expression of ER stress survival signals implies that HL precursor cells have overcome the ER stress imposed on tumorigenesis  ------------  44
      4.4.3. EBV-LMP1 enhanced expression of ER stress survival signals  ---  45
      4.4.4. Expression of ER stress signals in EBV-negative HL cases  ---------  45
    4.5. Conclusions and perspectives  --------------------------------------------------  46 
5. REFERENCES  ---------------------------------------------------------------------------  48
6. TABLES  ------------------------------------------------------------------------------------  58
    Table 1. Hodgkin lymphoma, by subtype, diagnosed in Taiwan at NCKUH 
and VGH, between 1982 and 2007  -------------------------------------  58
    Table 2. Comparison of HL subtypes and EBV association over time in Taiwan
    and in previous studies from Western countries  --------------------  59
    Table 3. The shift of frequency of EBV-positive HL towards older patients --- 60
    Table 4. The distribution and clinical features of 46 Vietnamese childhood HL cases  --------------------------------------------------------------------------  61
    Table 5. Patterns of subcellular localization of cyclin A in different types of LMP1-positive HL cells  --------------------------------------------------  63
    Table 6. Patterns of subcellular localization of cyclin A in different types of LMP1-negaitve HL cells  --------------------------------------------------  64
    Table 7. Increased multinucleated L-428 cells by LMP1 transfection over time
            ------------------------------------------------------------------------------------  65
    Table 8. The results of EBER in situ hybridization and immunohistochemical stains  -------------------------------------------------------------------------  66
    Table 9. Clinicopathologic parameters affecting survival  ---------------------  67
    Table 10. Detection rate of EBV in HL in different series  ---------------------  68
7. FIGURES  ----------------------------------------------------------------------------------  70
    Figure 1. Immunohistochemical staining and EBER1 in situ hybridization for HL cases shows positive signals in tumor cells with larger nuclear appearances  -----------------------------------------------------------------  70
    Figure 2. EBER in situ hybridization for HL cases shows positive signals in nuclear or nucleolar regions with large nuclear appearances consistent with tumor cells  -----------------------------------------------  71
    Figure 3. NLPHL case positive for EBER shown by serial sections  ---------  72
    Figure 4. The distribution of EBV positivity in an IM case shown by serial 
sections  -----------------------------------------------------------------------  73
    Figure 5. Different staining patterns of LMP1 in variant HL cells  ----------  74
    Figure 6. Five different staining patterns of cyclin A in HL cells  ------------  75
    Figure 7. No difference in the staining patterns of CD30 and CD99 between 
H and RS cells  --------------------------------------------------------------  76
    Figure 8. LMP1 transfection increases cytoplasmic expression of cyclin A 
in L-428 cells  ----------------------------------------------------------------  77
    Figure 9. Staining patterns of ER stress markers in HL cells  ----------------  79
    Figure 10. LMP1 transfection increases expression of GRP78 and XBP1 in 
L-428 cells  -----------------------------------------------------------------  80
    Figure 11. A model for the morphogenesis of H, RS, and mummified cells 
in HL  ------------------------------------------------------------------------  81 
8. APPENDIX  --------------------------------------------------------------------------------  82
    Publication list for dissertation  -----------------------------------------------------  82
9. CURRICULUM VITAE  ----------------------------------------------------------------  83
    Publications  -----------------------------------------------------------------------------  86
    Conference papers  ---------------------------------------------------------------------  92
                                    

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