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研究生:王雅麗
研究生(外文):Ya-Li Wang
論文名稱:由自體免疫抗體觀點探討牙周病病菌與紅斑性狼瘡之關聯
論文名稱(外文):The Association of Periodontal Pathogens and Systemic Lupus Erythematosus from the Viewpoint of Autoimmune Antibodies
指導教授:陳漪紋
口試委員:許秉寧
口試日期:2013-06-28
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床牙醫學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:43
中文關鍵詞:紅斑性狼瘡抗心磷脂抗體牙周病牙周病致病菌β2 Glycoprotein I
外文關鍵詞:Systemic lupus erythematosusanti-cardiolipin antibodyβ2Glycoprotein Iperiodontal diseaseperiodontal pathogen
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研究背景:文獻報告指出紅斑性狼瘡病人的血清中常能檢驗出自體免疫抗體抗心磷脂抗體的存在。抗心磷脂抗體屬於抗磷脂抗體中的一群,主要和血栓的產生有關係。當抗心磷脂抗體要與心磷脂結合時需要磷脂結合蛋白β2 Glycoprotein I 的存在才能和心磷脂結合。近年來也有研究指出β2 Glycoprotein I 上的TLRVYK蛋白序列其實才是抗心磷脂抗體的target antigen。此外,β2 Glycoprotein I 有抑制凝血的功能,若自體免疫抗體和β2 Glycoprotein I結合則會抑制其凝血的功能,進而促進血栓的形成。另一方面,牙周致病菌具有和TLRVYK類似的蛋白序列有可能在感染牙周致病菌的病人身上引發自體免疫抗體的產生,因此本實驗將從自體免疫抗體的角度探討牙周病致病菌的存在與紅斑性狼瘡疾病嚴重程度的相關性。
材料與方法:59位紅斑性狼瘡病人及35位健康者參與實驗。所有受試者皆接受臨床牙周檢查,並收集其唾液,牙菌斑以及血清。紅斑性狼瘡病人依據“systemic lupus erythematosus disease activity index” (SLEDAI)分為疾病活性不穩定31位,穩定28位。爾後利用聚合酶鏈鎖反應偵測唾液及牙菌斑中牙周病致病菌Porphyromonas gingivalis (P. gingivalis), Treponema denticola (T. denticola),Aggregatibacter actinomycetemcomitans (A. actimomycetemcomitans)的存在,並透過酵素免疫分析法測量其血清中抗心磷脂抗體,以及anti-β2 Glycoprotein I antibodies的含量。再將蒐集的資料進一步進行統計分析。
結果:相較於健康者,紅斑性狼瘡病人的牙周病盛行率較高,anti-β2 Glycoprotein I antibodies 也比較高,並具有統計上的差異性。研究結果也發現無論是不穩定或是穩定紅斑性狼瘡病人,其牙周附連喪失、牙周囊袋深度都比健康者嚴重。另一方面,雖然未達統計上的顯著性,不穩定紅斑性狼瘡疾病的病人若患有牙周病,或是有牙周致病菌的存在都會使血清中傾向於檢測出較高的anti-β2 Glycoprotein I antibodies 。尤其是同時感染兩種細菌時更有抗體值升高的趨勢,並達到統計上的差異性。
結論:本實驗發現紅斑性狼瘡疾病活性不穩定的病人其牙周病破壞與升高的anti-β2 Glycoprotein I antibodies相關,牙周致病菌P. gingivalis和T. denticola可能會引發自體免疫抗體的產生。因此對於臨床上anti-β2 Glycoprotein I antibodies較高的紅斑性狼瘡病人可以建議其接受牙周檢查,若患有牙周病則透過牙周病治療減少牙周致病菌的存在,改善牙周的健康降低由感染而引發的自體免疫抗體產生,或許能改善紅斑性狼瘡病人可能會面臨的臨床併發症。


Introduction: It was reported Systemic Lupus Erythematosus (SLE) patients exhibited higher anti-cardiolipin (anti-CL) antibodies, a class of anti-phospholipid antibodies associated with thrombosis. Anti-CL antibodies required the presence of the plasma phospholipid binding protein, β2-Glycoprotein I (β2GPI), in order to bind cardiolipin molecule. β2-Glycoprotein I has been considered as the actual target antigen for autoimmune antibodies. Pathogenic anti-cardiolipin and anti- β2GPI antibodies could be induced by immunizing mice with Hemophilus influenzae or Neisseria gonorrheae, which bear peptide sequences homologous to the TLRVYK peptide of β2GPI. Periodontal bacteria also bear homologous peptide of TLRVYK; therefore, we hypothesize that periodontal bacteria might induce anti-CL or anti-β2GPI antibodies production through molecular mimicry.
Materials and Methods: 59 SLE patients and 35 healthy subjects were recruited in this study, and all subjects received periodontal examinations. The disease activity of SLE was classified into mild and moderate to severe groups based on the “systemic lupus erythematosus disease activity index” (SLEDAI). The presence of Porphyromonas gingivalis (P. gingivalis), Treponema denticola(T. denticola)and Aggregatibacter actinomycetemcomitans(A. actimomycetemcomitans)in saliva and plaque sample was detected by polymerase chain reaction. Serum Anti-CL and anti-β2GPI antibodies were examined using the enzyme-linked immunosorbent assay.
Results: Both two groups of SLE patients showed higher prevalence of periodontitis, more severe periodontal destruction and increased titers of serum anti-β2GPI antibodies compared with healthy subjects. Moderate to severe SLE patients with periodontitis seemed to exhibited higher anti-β2GPI antibodies than those without periodontitis. The level of anti-β2GPI antibodies was significantly higher in moderate to severe SLE patients who harboured T. denticola and P. gingivalis intra orally.
Conclusion: Elevated anti-β2GPI antibodies was associated with periodontal severity, especially in moderate to severe SLE patients. T. denticola and P. gingivalis might serve as exogenous antigens that elicit anti-β2GPI antibodies production. Anti-β2GPI antibodies might be used as a biomarker to detect periodontal diseases in SLE patients.



目錄
誌謝 I
中文摘要 II
Abstract IV
目錄 VI
圖表目錄 VIII
第一章 緒論 1
第一節 紅斑性狼瘡(Systemic Erythematosus Lupus) 1
1-1 紅斑性狼瘡 1
1-2 紅斑性狼瘡的臨床表現及診斷 1
第二節 抗磷脂症候群 (Antiphospholipid Syndrome, APS) 3
2-1 抗磷脂症候群 3
2-2 抗磷脂抗體 3
2-3 抗磷脂抗體與血管栓塞的關係 4
第三節 牙周病 6
第四節 牙周病與抗心磷脂抗體的關係 7
4-1 牙周病與抗心磷脂抗體的關係 7
4-2 牙周病致病菌與抗心磷脂抗體的關係 8
第二章 研究目的 10
第三章 實驗材料與方法 11
一、研究對象 11
二、臨床牙周檢查 11
三、細菌收集及藉由聚合酶鏈鎖反應檢測細菌 12
3-1 細菌收集 12
3-2 唾液及牙菌斑處理 12
3-3 聚合酶鏈鎖反應(Polymerase Chain Reaction, PCR) 13
3-4 瓊脂凝膠電泳分析 (Agarose gel electrophoresis) 13
四、血清中抗心磷脂抗體檢測與酵素免疫分析法(ELISA) 14
4-1 血液處理 14
4-2 酵素免疫分析法(ELISA) 14
五、統計分析 15
第四章 結果 17
一、 紅斑性狼瘡病人疾病嚴重程度分類 17
二、 紅斑性狼瘡病人與健康者的牙周健康狀況 17
1. 牙周病盛行率 17
2. 牙周病的嚴重程度 17
三、 紅斑性狼瘡病人與健康者的抗心磷脂抗體、anti-β2 glycoprotein I antibodies 分佈情況 18
1. 抗心磷脂抗體 18
2. Anti-β2 glycoprotein I antibodies 18
3. 抗心磷脂抗體與anti-β2 glycoprotein I antibodies 19
四、 牙周病與抗心磷脂抗體及anti-β2 glycoprotein I antibodies關係 19
1. 紅斑性狼瘡疾病嚴重程度與牙周病和抗心磷脂抗體的相關性 19
2. 紅斑性狼瘡疾病嚴重程度與牙周病和Anti-β2 glycoprotein I antibodies相 關性 19
五、 細菌與抗心磷脂抗體及anti-β2 glycoprotein I antibodies的關係 20
1. 細菌的盛行率 20
2. T. denticola與抗心磷脂抗體及anti-β2 glycoprotein I antibodies的關係 21
3. P. gingivalis與抗心磷脂抗體及anti-β2 glycoprotein I antibodies的關係 21
4. 同時感染P. gingivalis和T. denticola與抗心磷脂抗體及anti-β2 glycoprotein I antibodies的關係 22
六、 紅斑性狼瘡與風險因子的相關性 23
第五章 討論 24
參考文獻 37

圖表目錄

圖 一、紅斑性狼瘡疾病活性不穩定、穩定與健康者牙周破壞的比較 28
圖 二、紅斑性狼瘡疾病活性不穩定、穩定與健康者抗心磷脂抗體、Anti-β2 Glycoprotein I antibodies的比較 29
圖 三、Anti-β2 Glycoprotein I antibodies 與ESR及PLT的相關性 30
圖 四、牙周病與紅斑性狼瘡病人不穩定、穩定及健康者在抗心磷脂抗體、Anti-β2 Glycoprotein I antibodies 的相關性 31
圖 五、T. denticola與紅斑性狼瘡病人不穩定、穩定及健康者在抗心磷脂抗體、Anti-β2 Glycoprotein I antibodies 的相關性 32
圖 六、P. gingivalis與紅斑性狼瘡病人不穩定、穩定及健康者在抗心磷脂抗體、Anti-β2 Glycoprotein I antibodies 的相關性 33
圖 七、混合感染P. gingivalis和T. denticola與紅斑性狼瘡病人不穩定、穩定及健康者在抗心磷脂抗體、Anti-β2 Glycoprotein I antibodies的相關性 34

Table 1. Demographic and clinical conditions of the studied cohorts 35
Table 2. Laboratory data of SLE patients 35
Table 3. Association of risk factors with SLE in a logistic regression model. Independent variables include Age, gender, anti-β2GPI abs, clinical attachment loss, and the infection of T. denticola and P. gingivalis 36
Table 4. Association of risk factors with SLE in a logistic regression model. Independent variables include Age, anti-β2GPI abs, clinical attachment loss, and the infection of T. denticola and P. gingivalis 36

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