臺灣博碩士論文加值系統

中 文 摘 要
目的: 幼年型類風濕性關節炎的病理機轉至今尚未明瞭，其主要病理變化是關節內的慢性滑膜炎，最近幾年已有相當程度的證據顯示白血球聚集到關節引起發炎反應的過程很可能是由某些趨化激素來調控。本研究的目的乃探討趨化激素RANTES(regulated upon activation, normal T cell expressed and secreted)與MCP-1(monocyte chemoattractant protein-1) 在幼年型類風濕性關節炎的表現、關節液對單核白血球的趨化能力，同時探討RANTES與MCP-1之基因多樣性在幼年型類風濕性關節炎的重要性。
方法: 利用酵素連結免疫螢光吸附分析法(ELISA)來分析病童血清及關節液中趨化激素(RANTES與MCP-1)的濃度。運用modified Boyden chamber來分析病童關節液對單核白血球的趨化能力，再分析抗RANTES單株抗體與抗MCP-1單株抗體是否能中和關節液對單核白血球的趨化能力，以探討趨化激素扮演的角色。並應用聚合酶連鎖反應結合限制酶切割片段長度多型性分析(PCR-RFLP)的方法來做病童及對照組兒童的基因型態分析。
結果: 三種亞型的幼年型類風濕性關節炎病童，其疾病活化期的RANTES血清濃度都有明顯升高的情形，平均濃度以全身型為最高。而MCP-1血清濃度則是在全身型病童特別升高，而且與發燒等全身性症狀有顯著相關。儘管RANTES與MCP-1的血清濃度在治療後明顯下降，但兩者在緩解期的血清濃度依然比正常人來得高。緩解期的血清RANTES濃度與緩解時間長短呈現負相關。若緩解期血清RANTES濃度較低則緩解時間長，若緩解期血清RANTES濃度持續偏高，疾病常常很快復發。RANTES血清濃度與實驗室指標包含C–反應蛋白(CRP)濃度、血紅素數值、白血球總數、血小板總數呈顯著相關，MCP-1血清濃度則是和白血球總數與血清儲鐵蛋白(ferritin)濃度有相關性。RANTES與MCP-1在關節液中的濃度也有明顯升高。抗RANTES單株抗體與抗MCP-1單株抗體皆能有效抑制關節液對單核白血球的趨化能力。
幼年型類風濕性關節炎病童組帶有RANTES -28G/G基因型的比率明顯比健康對照組來的高。RANTES -28C/G基因多樣性與緩解時間長短呈現顯著相關，首次緩解期時間在RANTES -28G對偶基因病童組只有那些帶正常RANTES -28C/C基因型病童的49%。RANTES -28C/G基因多樣性也和關節內注射類固醇(triamcinolone hexacetonide)的療效持續時間呈現相關性，帶有RANTES -28G對偶基因的病童療效持續時間明顯較短。RANTES -403G/A 和MCP-1 -2518A/G基因多樣性的出現頻率在幼年型類風濕性關節炎病童以及健康對照組之間並無顯著差異。
結論: 我們的研究顯示趨化激素RANTES在幼年型類風濕性關節炎三種亞型的病理機轉皆扮演重要的角色，MCP-1則在全身型特別重要。血清趨化激素濃度是幼年型類風濕性關節炎疾病活動度的敏感指標。RANTES -28C/G基因多樣性是幼年型類風濕性關節炎的遺傳危險因子，值得注意的是這個基因多樣性也與緩解後的早期復發以及關節內類固醇注射的療效持續時間長短有顯著相關性。

ABSTRACT
OBJECTIVE. Juvenile rheumatoid arthritis (JRA) is characterized by large numbers of infiltrating leukocytes in inflamed joints. Although the molecular signals that control the recruitment of leukocytes to the joints have not been fully characterized, this process is believed to be controlled by certain chemokines. The objective of this study is to longitudinally investigate serum and synovial fluid (SF) levels of regulated upon activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), in vitro migration of mononuclear cells towards SF, as well as the roles of RANTES and MCP-1 gene polymorphisms in patients with JRA.
METHODS. Serum and SF levels of RANTES and MCP-1 were determined by an enzyme-linked immunosorbent assay (ELISA). Chemotaxis was performed using the modified Boyden chamber method, which was followed by neutralization experiments with anti-RANTES and anti-MCP-1 monoclonal antibodies. RANTES and MCP-1 gene polymorphisms were genotyped using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay.
RESULTS. Serum RANTES levels were significantly increased in all onset subtypes of JRA, with the highest levels present in systemic-onset JRA. Serum MCP-1 levels were significantly elevated in patients with systemic-onset JRA and associated with current systemic features. Although serum levels of RANTES and MCP-1 decreased significantly after treatment, RATNES and MCP-1 levels during disease remission were still significantly higher in JRA patients than in controls. A relationship was found between serum RANTES levels during remission and the duration of clinical remission, with low levels being associated with prolonged clinical remission and high levels with shorter clinical remission. Serum RANTES levels correlated with C-reactive protein (CRP) concentrations, hemoglobin values, white blood cell (WBC) counts and platelet counts, whereas serum MCP-1 levels correlated with WBC counts and serum ferritin levels. Levels of RANTES and MCP-1 in SF were elevated as compared with levels in serum. SF chemotactic activity for mononuclear leukocytes was significantly inhibited by either anti-RANTES or anti-MCP-1 antibody.
JRA patients had significantly higher frequency of the RANTES -28G/G genotype, as compared with ethnically matched healthy controls. The RANTES -28C/G polymorphism was associated the duration of clinical remission, with patients carrying the RANTES -28G allele experiencing only 49% of the duration of remission in the RANTES -28C/C homozygous patients. The RANTES -28C/G polymorphism was associated with the duration of the clinical response to intraarticular triamcinolone injection, with patients carrying the RANTES -28G allele showing shorter response. No significant association between the RANTES -403G/A or MCP-1 -2518A/G polymorphisms and JRA was found in this Chinese population.
CONCLUSION. RANTES is a key molecule in the pathogenesis of all onset groups of JRA, whereas MCP-1 is particularly important in systemic-onset JRA. Serum levels of these CC chemokines represent more highly sensitive markers of disease activity than conventional inflammation parameters. RANTES -28C/G polymorphism represents a genetic risk for JRA. It is noteworthy that this CC chemokine polymorphism was also associated with an early relapse of disease after clinical remission and a shorter response to intraarticular administration of corticosteroids.

TABLE OF CONTENTS
指導教授推薦書………………………………………………………………
口試委員會審定書……………………………………………………………
授權書………………………………………………………………………… iii
題獻…………………………………………………………………………… iv
致謝…………………………………………………………………………… v
TABLE OF CONTENTS……………………………………………………… vi
ABSTRACT (中文摘要)……………………………………………………… x
ABSTRACT (English)……………………………………………………… xii
LIST OF TABLES…………………………………………………………… xv
LIST OF FIGURES………………………………………………………… xviii
ABBREVIATIONS…………………………………………………………… xx
CHAPTER I INTRODUCTION.…………………………………………… 1
1.1 Review of Juvenile Rheumatoid Arthritis in the
Literature…………………………………………………………… 1
1.1.1 General Overview……………………………………………… 1
1.1.2 Diagnosis and Classification…………………………… 2
1.1.3 Epidemiology and Demographics………………………… 2
1.1.4 Clinical Features…………………………………………… 3
1.1.5 Etiology and Pathogenesis.……………………………… 5
1.1.6 Laboratory Parameters……………………………………… 6
1.1.7 Treatment and Outcome……………………………………… 8
1.2 The Burden of JRA in Taiwan………………………………… 10
1.2.1 Prevalence of JRA in Taiwan……………………………… 10
1.2.2 Characteristics of JRA in Taiwan……………………… 10
1.2.3 HLA-DRB1 Genotyping in Taiwanese Children with
JRA……………………………………………………………… 11
1.3 Overview of Chemokines……………………………………… 12
1.3.1 General Overview.…………………………………………… 12
1.3.2 Chemokine Subfamilies…………………………………… 13
1.3.3 Roles of Chemokines in Various Inflammatory
Diseases……………………………………………………… 13
1.4 Roles of RANTES and MCP-1 in Chronic Arthritis… 14
1.4.1 RANTES and Its Role in Animal Models of
Arthritis……………………………………………………… 14
1.4.2 MCP-1 and Its Role in Animal Models of Arthritis 15
1.4.3 Studies of RANTES and MCP-1 in Adult Rheumatoid
Arthritis.……………………………………………………… 15
1.4.4 RANTES and MCP-1 as Immunoregulators………………… 16
1.4.5 Roles of RANTES and MCP-1 in JRA Remain Unclear 18
1.5 RANTES and MCP-1 Gene Polymorphisms…………………… 18
1.6 Tables in the Introduction………………………………… 20
1.7 Figures in the Introduction………………………………… 28
CHAPTER II AIMS OF THE STUDY.………………………………… 32
CHAPTER III PATIENTS AND METHODS…………………………… 35
3.1 Patients and Controls………………………………………… 35
3.2 Measurement of RANTES………………………………………… 37
3.3 Measurement of MCP-1………………………………………… 39
3.4 In Vitro Migration of PBMCs towards SF……………… 40
3.5 DNA Extraction…………………………………………………… 42
3.6 enotyping…………………………………………………………… 43
3.6.1 Genotyping of RANTES –28 C/G and –403 G/A
polymorphisms…………………………………………………… 44
3.6.2 Genotyping of MCP-1 –2518 A/G polymorphism……… 45
3.7 Statistical Analysis…………………………………………… 46
CHAPTER IV RESULTS…………………………………………………… 48
4.1 Serum Levels of RANTES and MCP-1 in Patients with
Active JRA…………………………………………………………… 48
4.2 Relationship of Serum RANTES and MCP-1 Levels with
Disease Activity………………………………………………………… 49
4.3 Correlation of Serum Levels of RANTES and MCP-1 with
Laboratory Parameters and Clinical Variables……………… 51
4.4 SF Levels of RANTES and MCP-1 in Patients with JRA 51
4.5 In Vitro Migration of PBMCs toward SF…………………… 51
4.6 RANTES –28 C/G and –403 G/A Polymorphisms in JRA
Patients and Controls…………………………………………… 52
4.7 MCP-1 –2518 A/G Polymorphism in JRA Patients and
Controls……………………………………………………………… 54
4.8 Association of RANTES and MCP-1 Polymorphisms with
Laboratory Parameters and Clinical Variables……… 54
4.9 Association of RANTES and MCP-1 Polymorphisms with
Outcome after Remission……………………………………… 55
4.10 Association of RANTES and MCP-1 Polymorphisms
with Response to Intraarticular Triamcinolone
Injection………………………………………………………… 57
CHAPTER V DISCUSSION…………….………………………………… 59
CHAPTER VI CONCLUSION……………………………………………… 72
REFERENCES………………………………………………………………… 73
TABLES OF THE STUDY.………………………………………………… 87
FIGURES OF THE STUDY...…………………………………………… 101
APPENDIX..………………………………………………………………… 109
Appendex A. List of Publications……………………………… 109
Appendex B. List of Awards……………………………………… 113
Appendex C. Attached Publications…………………………… 114

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