胃浸潤T細胞在幽門螺旋桿菌胃炎之 免疫致病機轉

Gastric infiltrating T cells in immunopathogenesis of Helicobacter gastritis

吳怡瑩(Yi-Ying Wu)

指導教授 ： 許秉寧

國立臺灣大學/醫學院/免疫學研究所/博士(2006年)

https://doi.org/10.6342/NTU.2006.01301

摘要

胃幽門螺旋桿菌，一個人類重要且常見的病毒，是慢性胃炎，消化潰瘍疾病的致病因子。最近的研究已經顯示胃上皮的細胞apoptosis 在胃幽門螺旋桿菌感染期間會增加。感染胃幽門螺旋桿菌會增加的胃上皮細胞的apoptosis。胃幽門螺旋桿菌感染已經被建議參與慢性胃炎的致病機轉，在消化的潰瘍和胃的 neoplasia 中扮演重要角色。 胃幽門螺旋桿菌感染可以藉由透過和浸潤 T 細胞的互動增加胃的上皮細胞 apoptosis 引起胃部的黏膜損害。這些結果意味著胃幽門螺旋桿菌感染在胃上皮的細胞 apoptosis扮演一個重要的角色。為了探討胃浸潤淋巴球在胃幽門螺旋桿菌感染期間在胃的上皮損害所扮演的角色。我們首先探討TRAIL引起人類的胃上皮細胞apoptosis。TRAIL是TNF superfamily molecule的成員，而且可以是effector T 細胞的一個分子。所以我們去探討是否胃幽門螺旋桿菌感染組織中胃浸潤 T細胞的表面是否有表現TRAIL。我們的結果顯示胃幽門螺旋桿菌可以改變人類的胃上皮的細胞對於TRAIL的感受性，而造成胃上皮的細胞的apoptosis。胃幽門螺旋桿菌改變人類的胃上皮的細胞對於TRAIL的感受性造成胃上皮的細胞的apoptosis是依賴和有活力細菌的直接接觸，但是不是依賴胃幽門螺旋桿菌的毒力因子，CagA 和 VacA。更進一步的研究顯示胃浸潤 T細胞表現TRAIL在他們的細胞表面上。我們的結果發現胃幽門螺旋桿菌可以改變宿主胃上皮細胞對於亡受容器(TRAIL)的敏感性，藉由和細菌的直接接觸導致胃上皮細對(TRAIL)的敏感改變造成胃上皮細胞的apoptosis，對於胃幽門螺旋桿菌的感染提供一個新方向。
為了要了解胃幽門螺旋桿菌發炎反應的機制和了解在胃幽門螺旋桿菌感染期間胃浸潤淋巴球進入胃的黏膜召集情形。我們之後探討胃浸潤淋巴球的 chemokine 受器的表現，更進一步在胃幽門螺旋桿菌感染胃炎期間探討chemokine�chemokine 受器交互作用在胃的浸潤淋巴球的招募角色。胃的浸潤淋巴球表現 Th1 chemokine 受器 CXCR3 ，CCR5 和 CXCR6 但不表現Th2 chemokine 受器 CCR3。 除此之外，胃的 T 細胞表現高量的CCR6 。最近的研究已經發現CCR6 是specificβ-chemokine receptor，ligand為 CCL20(MIP-3α）選擇性的在一些記憶 T 細胞上表現而且可能扮演在胃的發炎期間驅化淋巴球移動的角色。我們更進一步在胃幽門螺旋桿菌胃炎的組織中探討CCR6 和它的 ligand CCL20所扮演的角色 。我們的結果指出 chemokine CCL20的表現在 inflamed 的胃組織顯著地增加，而且 CCL20 的表現在有胃幽門螺旋桿菌和proinflammatory cytokines IL-1β和 TNF-α 刺激下會更顯著地增加。而且，從胃的浸潤 T 細胞對於recombinant CCL20 濃度上升有更好的驅化效果的結果顯示在 CCL20/CCR6 之間的交互作用可能扮演在胃幽門螺旋桿菌胃炎期間的chemokine-mediated lymphocyte trafficking扮演重要的角色。所以，我們的研究顯示胃幽門螺旋桿菌的感染，它可以使胃上皮的細胞對TRAIL敏感增加造成胃上皮細胞的 apoptosis，經由胃的浸潤 T 細上表現的TRAIL，之後發炎的組織中在也可藉由 chemokine 受器�chemokine 之間的交互作用引誘胃浸潤 T 細胞到達發炎的部位，導致胃的黏膜損害。我們的研究顯示 CCR6/CCL20 在胃幽門螺旋桿菌的感染所引起的免疫致病機轉扮演著重要的角色。

關鍵字

胃浸潤T細胞 ； 胃炎 ； 幽門螺旋桿菌

並列摘要

H. pylori, a common pathogen of human, is the leading cause of chronic gastritis and peptic ulcer diseases. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis, peptic ulcer and gastric neoplasia. H. pylori infection could induce gastric mucosa damage by increasing gastric epithelial cell apoptosis through interaction with infiltrating T cells. These findings suggest a role for immune-mediated apoptosis of gastric epithelial cells during H. pylori infection. To investigate role and mechanisms of gastric infiltrating lymphocytes in immune-mediated gastric epithelium damage during H. pylori infection, we first investigate role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF superfamily molecule with apoptosis-inducing activity and could serve as an effector molecule for T cells, in inducing apoptosis in human gastric epithelial cells and to assess the expression of TRAIL on the surface of infiltrating T-cells in H pylori-infected gastric mucosa. Our results demonstrated that H. pylori could sensitize human gastric epithelial cells, confer susceptibility to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H pylori was dependent upon direct cell contact of viable bacteria, but not the virulent factors, CagA and VacA of H pylori. Further studies demonstrated that infiltrating T-cells in gastric mucosa expressed TRAIL on their surfaces. Our results indicate that H. pylori could modulate host cell apoptosis and confer sensitivity to death receptor-induced apoptosis. Modulation of host cell sensitivity to apoptosis by bacterial interaction adds a new dimension to the immunopathogenesis of H pylori infection.
In order to understand the mechanisms of induction of inflammatory response and recruitment of infiltrating lymphocytes into gastric mucosa during H. pylori infection, we then investigate the expression of chemokine receptors in gastric infiltrating lymphocytes and the upregulation of chemokines in inflamed gastric tissues, and to further define role of chemokine/chemokine receptor interaction in recruitment of gastric infiltrating lymphocytes during H. pylori infection. The gastric infiltrating lymphocytes express Th1 chemokine receptors CXCR3, CCR5 and CXCR6 but not Th2 chemokine receptor CCR3. In addition, the gastric T cells express significant high level of CCR6. Recent studies have demonstrated that CCR6, the specificβ -chemokine receptor for CCL20 (MIP-3α), is selected expressed on some memory T cells and may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. We further investigate CCR6 and its ligand CCL20 in inducing gastric inflammation during H. pylori infection. Our results indicated that expression of chemokine, CCL20 was markedly increased in inflamed gastric tissues, and the production of CCL20 was upregulated in response to H. pylori when stimulated by proinflammatory cytokines IL-1β and TNF-α. Moreover, the gastric infiltrating T cells isolated from gastritis tissues migrated toward recombinant CCL20 in a dose dependent manner in chemotaxis assay. Our results imply that interaction between CCL20/CCR6 may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. Taken together, our study indicates that during H. pylori infection, it could sensitize gastric epithelial cells to TRAIL-mediated apoptosis, via interaction with TRAIL from gastric infiltrating T cells subsequently induced by interaction between chemokine receptor /chemokine, in particular, CCR6/CCL20 in inflamed gastric tissues induced by H. pylori, leading to gastric mucosa damage. Our study suggests a role of CCR6/CCL20 in the immunopathogenesis of H pylori infection.

並列關鍵字

gastric infiltrating T cells ； gastritis ； Helicobacter pylori

參考文獻

Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, Tsubokawa M, Tohyama Y, Maeda S, Omata M, Suzuki T, Sasakawa C. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 2000; 191: 593-602.

Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000;406:309-314.

Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, Brooks EG, Graham DY, Reyes VE, Ernst PB. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology 1998; 114: 482-492.

Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and regional immunity. Adv Immunol 1999;72:209-253.

Baggiolini M. Chemokines and leukocyte traffic. Nature 1998;392:565-568.