血小板的重要生理功能之一是能夠在傷口處形成血栓，達到止血的目的。而近來研究顯示，血小板在先天免疫中也扮演著重要角色。我們對於血小板和幽門螺旋桿菌間的興趣起源於一些血小板低下症的人同時也有幽門螺旋桿菌的感染；而這類病患有些人在除去胃幽門螺旋桿菌後，血小板數目會回升。雖然先前的研究已經知道有些幽門螺旋桿菌菌株會和血小板黏合，而引起血小板的活化，產生凝集反應以及血小板的凋亡反應。然而，對於血小板在參與先天免疫的巨噬細胞除去胃幽門螺旋桿菌所扮演的角色以及它們和血小板低下症的關係，尚未完全明瞭；因此本研究即進一步探討此關係。我們首先觀察以胃幽門螺旋桿菌或以胃幽門螺旋桿菌的脂多醣 (LPS) 感染血小板，結果它們都會增加血小板漿膜上磷脂絲氨酸 (PS) 的表現量，而這也是巨噬細胞在吞噬過程辨識的分子標記之一。接著，在未加入血清的環境中，以胃幽門螺旋桿菌感染血小板，可以小幅度的促進巨噬細胞對於血小板的吞噬；但如以脂多醣 (LPS) 刺激血小板，卻會減少巨噬細胞對於血小板的吞噬作用。最後我們探討胃幽門螺旋桿菌的抗體對吞噬作用的影響。結果顯示當血清中有胃幽門螺旋桿菌抗體時，巨噬細胞對被胃幽門螺旋桿菌黏合的血小板會產生明顯的吞噬作用。因此，我們確認當血小板被胃幽門螺旋桿菌感染時，經由胃幽門螺旋桿菌抗體參與的先天免疫反應，啟動了巨噬細胞的吞噬作用，而這也是導致血小板數目減少的一種途徑。先前我們實驗室已經提出的有關胃幽門螺旋桿菌的感染會造成血小板凝集和凋亡反應，再加上本研究證實的巨噬細胞吞噬作用的綜合結果，應該可以明確的提供醫生，對於長期罹患不知原因的血小板低下症而且有胃幽門螺旋桿菌感染的患者，在診斷與治療上一個新的方向。

One of the most important physiological functions of platelets (PLTs) is clotting in the wound. Recent studies have revealed that PLTs also play important roles in innate immunity. We’re interested in the association between H. pylori and PLTs due to patients with thrombocytopenia often accompanied with H. pylori infection. There is growing evidence showed that the PLTs count recovered after H. pylori eradication therapy. It’s known that adhesion of some strains of H. pylori to PLT leaded to PLT activation, aggregation and apoptosis. However, the role of PLT in the innate immunity of macrophage eliminating H. pylori, and in the association between phagocytosis and H. pylori-induced thrombocytopenia remains unclear. We therefore investigated the association between the H. pylori infected PLTs and the uptake of PLTs by macrophage in this studies. Firstly, it’s observed that the expression of phosphatidylserine (PS), a molecular marker for macrophage clearance, increased on washed PLTs in response to H. pylori and lipopolysaccharide (LPS) of H. pylori stimulation. Secondly, the uptake of H. pylori infected washed PLTs by macrophage was slightly enhances, but it was slightly decreased when LPS was used instead of H. pylori. Finally, we investigated the role of H. pylori antibody. Results showed that H. pylori positive sera significantly enhanced the phagocytosis of washed PLTs in response to some strains of H. pylori infection. Our results suggest the increased uptake of PLTs-H. pylori by macrophage was mainly IgG-mediated. It would lead to decrease in platelet counts. Our previous data on H. pylori-induced PLTs aggregation and apoptosis and the results of this study will provide further understandings on the pathogenesis of H. pylori-induced thrombocytopenia. It will further assist physicians in diagnosis and making therapeutic decisions on the H. pylori infected patients with unknown reason thrombocytopenia.

論文審定書 i
誌謝 ii
中文摘要 iii
英文摘要 iv
縮寫表 ix
壹、 緒論 1
一、 血小板 1
1-1血小板生成 1
1-2血小板的組成 2
1-3血小板的功能 2
1-4血小板與免疫反應 (Immune response) 4
1-5血小板的相關疾病 5
二、 胃幽門螺旋桿菌 (Helicobacter pylori) 6
2-1 胃幽門螺旋桿菌的感染機轉 6
2-2 胃幽門螺旋桿菌的毒性因子 7
2-3 胃幽門螺旋桿菌的感染率與相關疾病 9
貳、 研究目的 10
參、 實驗材料與方法 13
一、 細胞培養 (Cell cuture) 13
1-1 實驗材料 13
1-2細胞培養液配置 13
1-3 實驗方法 14
二、 血小板及血清的製備 (Platelet and serum preparation) 15
2-1實驗材料 15
2-2實驗溶液配製 15
2-3實驗方法 15
三、 幽門螺旋桿菌之製備 (H. pylori preparation) 16
3-1實驗材料 16
3-2實驗方法 16
四、 分析磷脂絲氨酸表現 (Phosphatidylserine exposure) 實驗 17
4-1實驗材料 17
4-2實驗試劑配製 17
4-3實驗方法 18
五、 體外吞噬實驗 (In vitro Phagocytosis) 18
5-1實驗材料 18
5-2實驗溶液配製 19
5-3實驗方法 19
肆、 結果 22
一、 H. pylori 誘發血小板的 PS 表現 22
二、 LPS 誘發血小板的 PS 表現 24
三、 H. pylori與 LPS 對於吞噬血小板的影響 26
四、 含 H. pylori 抗體的血清能夠增強吞噬血小板的作用 28
伍、討論 30
陸、 參考文獻 34
柒、 未來工作 40
捌、 附錄 41

圖次
圖1-1、血小板生成示意圖 1
圖1-2、血小板活化與止血機轉 4
圖1-3、胃幽門螺旋桿菌感染胃黏膜層的機轉。 7
圖2-1、血小板感染 H. pylori 時，PS 的表現量。 10
圖2-2、血小板感染 H. pylori 時，細胞膜突起的現象。 11
圖2-3、血小板感染 H. pylori 時，caspase 的活化現象。 12
圖4-1、當 H. pylori 感染血小板時，血小板細胞膜上 PS 表現量。 23
圖4-2、當 H. pylori LPS 感染血小板時，血小板細胞膜上 PS 表現量。 25
圖4-3、當 H. pylori 與 LPS 感染血小板時，巨噬細胞對血小板的吞噬。 27
圖4-4、含 H. pylori 抗體的血清會調節吞噬血小板的作用。 29

表次
表8-1、H. pylori 誘發血小板的 PS 表現 (原始資料)…………………………… 41
表8-2、LPS 誘發血小板的 PS 表現 (原始資料)………………………………..... 42
表8-3、H. pylori 與 LPS 對於吞噬血小板的影響 (原始資料)…………………... 43
表8-4、含 H. pylori 抗體的血清能夠增強吞噬血小板的作用 (原始資料)……... 44

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