胃幽門螺旋桿菌感染造成免疫組織相容性複合體相關抗原呈現系統被丙型干擾素刺激後阻斷作用的探討

Helicobacter pylori is a gram-negative anaerobic bacterium which causes gastric ulcers in the stomach. A characteristic pathogenesis feature of H. pylori-caused gastric ulcers is vacuolation of gastric epithelial cells, which is associated with unresolved chronic inflammation in the course of the disease. There are many H. pylori virulence factors, such as VacA and CagA. These virulence factors may be responsible for immune suppression by down-regulating the expression of antigen presentation components, or changing the distribution of the MHC class I and class II molecules through altering intracellular vesicle trafficking. In our study, we have found antigen processing machinery (APM) components TAP1 and TAP2 were down-regulated both at the transcriptional and translational levels along with down-regulation of STAT promoter activity and of the IFN- responsive genes IRF-1 and GBP2. TAP1 and TAP2 down-regulation was corrected by a VacA inhibitor NPPB, suggesting the role of vacuolation in H. pylori-induced TAP down-regulation. Interestingly, both the level and distribution of MHC class II molecules were disrupted in H. pylori-infected HeLa cells. These MHC class II molecules were found to aggregate within H. pylori-induced vacuoles, where proteolytic processing was interrupted. These results and the co-localization of MHC class II molecules and their chaperon DM within H. pylori-induced vacuoles imply the presence of unstable, peptide-free MHC class II molecules which were transported to the cell surface poorly. Taken together, our results indicate that both MHC class I and MHC class II presenting antigen machinery were disrupted by H. pylori, thus impairing the presentation of endogenous peptides and exogenous antigens to CD8+ and CD4+ T cells. These findings may explain why H. pylori can escape host immune attack and may suggest strategies to treat gastric diseases induced by H. pylori.

關鍵字

胃幽門螺旋桿菌；免疫組織相容性複合體；丙型干擾素刺激

並列摘要

胃幽門螺旋桿菌是一種在胃部造成胃潰瘍的格蘭氏陰性菌。胃幽門螺旋桿菌造成胃潰瘍的發病特徵是讓胃表皮細胞空泡化，這也跟此疾病無法解決的慢性發炎有關。胃幽門螺旋桿菌有許多致病因子就像是VacA和CagA。這些致病因子可能負責參與免疫逃避藉由降低調控組織相容性複合體第一型抗原呈現構成分子的表現或著藉由改變免疫組織相容性複合體第二型的分佈透過細胞內的囊泡運輸。在我們的研究中，受胃幽門螺旋桿菌感染的上皮細胞中抗原呈現構成分子中的TAP1和TAP2在轉錄和轉譯層面被明顯的下調。然而在受胃幽門螺旋桿菌感染的上皮細胞中，大部分受丙型干擾素刺激的基因都會被胃幽門螺旋桿菌下調藉由降低STAT啟動子的活性。這種TAP1和TAP2的下調作用卻會被VacA的抑制劑NPPB給回復回來。此外，組織相容性複合體第二型的分佈也會受到胃幽門螺旋桿菌的干擾作用而聚集在細胞內的囊泡中。這暗示沒有胜肽可以嵌到免疫組織相容性複合體第二型中，空的免疫組織相容性複合體第二型是不穩定的且很難被送到細胞表面。總結，免疫組織相容性複合體第一型和第二型兩者的抗原呈現機制都被胃幽門螺旋桿菌干擾，所以不管內源性或著胞吞的胜肽都很難被呈現到細胞表面去刺激CD4+或CD8+淋巴細胞。我們推測這是胃幽門螺旋桿菌逃避寄主免疫攻擊的機制之一。藉由清楚了解這些機制，我們可以找出防止胃幽門螺旋桿菌造成的胃疾方法。

並列關鍵字

Helicobacter pylori ； gastric ulcers ； MHC class I ； MHC class II

參考文獻

1. Cover TL et al. 1991. Effect of Urease on HeLa Cell Vacuolation Induced by Helicobacter pylori Cytotoxin. Infect and Immun 59:1264-1270.

2. Yahiro K et al. 2004. Essential Domain of Receptor Tyrosine Phosphatase (RPTP) for Interaction with Helicobacter pylori Vacuolating

Cytotoxin. J Biol Chem 279: 51013–51021.

3. Tobin NP et al. 2008. Helicobacter pylori-induced inhibition of vascular endothelial cell functions: a role for VacA-dependent nitric oxide reduction. Am J Physiol Heart Circ Physiol 295: H1403–H1413.

4. McClain, MS et al. 2000. Acid activation of Helicobacter pylori vacuolating

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胃幽門螺旋桿菌感染造成免疫組織相容性複合體相關抗原呈現系統被丙型干擾素刺激後阻斷作用的探討

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