幽門桿菌是一隻革蘭氏陰性螺旋菌，生活在微需氧的環境下。在世界上，感染幽門桿菌的盛行率超過了百分之50。在自然情況下，幽門桿菌能高度適應在人類胃黏膜處，藉由黏著胃上皮細胞、逃避宿主的免疫反應，並且進展到長期群居在胃中並傳染。已經有大量的研究証實，幽門桿菌的感染和不同的消化道疾病有相關，包括了胃發炎、消化道潰瘍、胃淋巴腺癌和胃黏膜相關淋巴瘤。最近的研究也指出，不同的消化道疾病除了由不同菌種的幽門桿菌所造成外，這些消化道疾病可能和人跟人之間所產生的異質免疫反應有關。其中重要的一個因子，對於產生這些不同的免疫反應，已經証實的有細胞素基因的多型性。在幽門桿菌感染所引起的黏膜發炎有一項特徵，就是會一直持續吸引中性球和單核球浸潤到胃部的固有層。而誘導這樣的反應是和一些發炎細胞素有相關的，例如感染幽門桿菌後的腫瘤壞死因子。發炎反應是在感染幽門桿菌後的一個特徵。發炎反應是對抗病原菌入侵的一個重要免疫反應。腫瘤壞死因子和它相關的淋巴毒素(又稱腫瘤壞死因子B)在細胞性和發炎性免疫中都參與在其中。在本篇研究中，我們調查在台灣的病人在得到幽門桿菌感染之後所造成的不同臨床症狀，是否和宿主本身所帶有腫瘤壞死因子啟動子多型形和淋巴毒素基因型多型性有關。由結果中顯示，腫瘤壞死因子啟動子多型性和幽門桿菌易感性之間沒有任何統計上的關連，但在有幽門桿菌感染的病人分析上，發現帶有-1031C 和-863 A對偶基因的病人，比起那些帶有-1031T 和-863 C的人，會有比較嚴重的中性球浸潤和比較高的潰瘍發生機率。

　　先前的研究指出在腫瘤壞死因子啟動子區域上的單一核酸多型性-863和-857，和轉錄因子接合上核酸的位置有重疊。我們進行了相似的 EMSA實驗在AGS細胞株上，也得到了相似的結果，為了去檢測胃腺上皮細胞核蛋白是否會和腫瘤壞死因子啟動子-1031位置相結合，我們也利用 EMSA實驗來檢測。結果指出，在帶有不同腫瘤壞死因子啟動子-1031情況下，會形成不同樣式的電泳圖型在不同的緩衝液系統中。如結果，這些核酸和蛋白質的結合，可以利用外加特定的核酸競爭，消除此一結合，但無法被其它不相關的核酸序列所競爭。為了更進一步去証實這些功能上的意義，我們也建築了腫瘤壞死因子帶有不同單一核酸多型性的報導基因，未來去進行實驗來釐清。除此之外，為了去証實幽門桿菌在臨床上所扮演的角色，可利用不同數量的幽門桿菌感染胃腺上皮細胞，來觀察影響情況。利用生物資訊學補助的資料庫，顯示出幾種可能的轉錄因子結合位，將來可利用 EMSA實驗來確定是何種轉錄因子結合上腫瘤壞死因子-1031位置。

　　在本篇研究中，發現了腫瘤壞死因子啟動子上，-1031和-863二個位置的多型性會和感染幽門桿菌後，造成嚴重的中性球浸潤發炎、影響胃中腫瘤壞死因子產生和潰瘍發生機率。而且，這一篇研究也發現了在腫瘤壞死因子啟動子-1031位置，存在一個未知的轉錄因子結合位，而這些生物功能的意義和臨床上的相關性，則需要更進一步的去証實。

　　Helicobacter pylori is a spiral Gram’s negative bacterium, living in microaerophilic environment. The prevalence of H. pylori infection is over 50 percent in the world. In natural condition, H. pylori is highly adapted to gastric mucosa by attachment to epithelial cells, evasion of the immune response, and that proceed to persistent colonization and transmission. Numerous studies have shown that the infection of H. pylori is related to different peptic diseases, including gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma (MALToma). Recent studies also indicate that the different peptic diseases can be caused different H. pylori strains, they also maybe relate to the heterogeneity of immune responses among different individuals. One of the significant contributing factors of different immune responses can be ascribed to the genetic polymorphisms of cytokine genes. A hallmark of H. pylori-triggered mucosal inflammation is the continuous recruitment with neutrophil and mononuclear cell infiltration to the gastric lamina propria. Such process is thought to be induced by inflammatory cytokine, e.g., TNF-� after H. pylori infection. Inflammation is a hallmark of H. pyloric infection. Inflammation is an important immune response against invasion of pathogen. TNF-α and related cytokines, lymphotoxin-α (LT-α or TNF-β) are involved in cellular and inflammatory immune reactions. In this study, we investigate whether the different clinical outcomes after H. pylori infection is related with the host’s genotype polymorphisms of TNF-A and LTA in Taiwan. The results show none of TNF-α promoter SNPs were related to the prevalence of H. pylori infection. In H. pylori infection patients, patients carry -1031C and/or -863A of the TNF-α promoter had more severe gastric neutrophiles infiltration and higher ulcer rate than those carry -1031T and -863C.

　　Previous studies have indicated that single nucleotide polymorphism (SNP) within TNF-α promoter region at -857, -863 coincides with the DNA motifs to which transcription factors bind. Similar results to those described previously were obtained when we performed electrophoresis mobility shift assay (EMSA) using double stranded oligomers containing SNP at -863(C/A) with nuclear extracts of AGS cell line. To demonstrate the biological significance of SNP at -1031 position, we also performed EMSA. The results indicate that double-stranded oligomers contain -1031T or -1031C alleles have different gel shift patterns in EMSA with different buffer system. The specificity of DNA-protein complexes are illustrated by the fact that they would disappear upon competition with self and different allele and but they are not competed by irrevalant oligomers. To further demonstrate its functional significance the concatemer of various alleles are constructed in luciferase reporter gene. Their clinical significance will be assessed in AGS cells infected with different moi of Hp. Bioinformatics-assisted database research has revealed several potential transcriptional factor biding site. They will be used in EMSA to identify the transcriptional factor binding to -1031.

　　Taken together, this study found TNFA promoter SNP on the -1031 and -863 loci are novel host factors related with the severity of gastric neutrophil inflammation, gastric TNF-α expression, and the risk of peptic ulceration after H. pylori infection. This study also suggest that a novel transcription factor may bind to TNFA promoter -1031binding site. Its functional significance and clinical relevance remain further investigation.

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