The 2005 Nobel Prize Helicobacter pylori 64 陳冠伃 62 陳治郡 80 楊昀達 91 鄭惟仁 60 陳安婕 75 黃俊諺 71 陳穎鈞 63 陳泊儒 59 郭人碩 指導助教 : 林博雅

Contents 得獎者簡介 幽門桿菌介紹 VacA 致病機制 急性慢性胃炎 CagA 致病機轉 Helicobacter 致癌機制 Helicobacter 檢驗與治療 影片總結

About the Laureates --- before they met

Barry J. Marshall Barry J. Marshall J. Robin Warren J. Robin Warren

After they met ---heading toward the Nobel prize

1981 Campylobacter-like organisms, CLO 1982 tissue culture & animal model 1984 human model 1989 Helicobacter pylori 2005 Nobel prize

Helicobacter pylori about 3 μ m in length and 0.5 μ m in diameter Gram-negative and microaerophilic Use flagella for motility

Secrete urease for surviving in acid environment. Spread from person to person through fecal-oral or oral-oral routes. Stomach acid Gastric epithelium

Flagella Secreted proteins VacA & CagA 1. 胃部黏膜細胞的毀損 2. 造成胃癌 3. 引起一連串的免疫機制 1.Adhesion 2.TFSS 系統 Urease 1. 使 Hp 能在胃部生存 2. 尿素檢驗法 - 胃是否有 Hp

Virulence factor flagellin （鞭毛蛋白） urease （尿素酶） adhesin （黏附素） vacuolating cytotoxin,VacA （空泡毒素） cytotoxin associated gene A,CagA （細胞毒素相 關蛋白）

Flagellin The principal flagellum substituent Switch between multiple flagellin genes Activity ＆ Toxicity

Urease

Adhesin Releases protease and phospholipase degrades the hydrophobic layer gastric acid erodes stomach Adhere to stomach cell

VacA Vacuolating cytotoxin A 30nm 87kD 1980 Timothy Cover H.pylori infects epithelial cells→vacuolation Oligomer Double layer 。 Single layer 。 6-7

VacA pathways Apoptosis Tight junction Vacuolation

Apoptosis

Vacuolation H+H+ V-ATPase Oligomerization Cl - Channel Apoptosis

Tight junction Inhibit T cell activation

Acute gastritisChronic gastritis

Acute gastritis Microphage Dendritic cell IL-12 Release IL-12 (Interleukin 細胞間白素 ) → activate T H 1 cells Positive feedback INF- γ Release INF(Interferon)-γ → attract more macrophages to the infected epithelial cells → inflammation Release IL-2 → activate T C Activate B cell (little) B cell

Dendritic cell IL-10 IL-12 Release IL-12 → activate T H 1 cells Chronic gastritis Release IL-10 → activate T H 2 cells → inactivate T H 1 cells INF- γ IL-4 B cell Microphage Release INF-γ → attract more macrophages to the infected epithelial cells → inflammation Release IL-4 → activate more B cells

Comparison AcuteChronic Activation of B cellslittlemuch Species of T H cellsT H 1 cells T H 1 cells 、 T H 2 cells IL-10 released by T H 2 cells will inactivate T H 1 cells → By contrast, T H 1 cells in chronic gastritis are less → Reduce the level of inflammation Inflammatory levelhighlow

CagA(cytotoxin associated gene A) an H. pylori virulence factor 1 1 a 120–145-kDa protein exists in 60%~70% H. pylori. CAG PATHOGENICITY ISLANDCAG PATHOGENICITY ISLAND (PAI) CAG PATHOGENICITY ISLAND 2 2 cagA-positive and cagA-negative strains. 3 TYPE IV SECRETION SYSTEM(TFSS) TYPE IV SECRETION SYSTEMTYPE IV SECRETION SYSTEM

TFSS

CagA pathways SH2 protein tyrosine phosphatase 2 (SHP-2) SH2 ： src homology 2 domains PTP ： protein tyrosine phosphatase

IL-8 assembles monocytes, neutrophils and ROS Leukocytes secrete a. IL-1β --- proinflammatory cytokines b. TNFα ---Tumer necrosis factor

Cag A Gastric epithelial cells IL-8 ROS aggregation White blood cells aggregation Affect cell physiolgy More white blood cells aggregation Chronic gastritis White blood cells release cytokines IL-1β Secrete gastric juice↓ TNFα COX-2↑ More serious inflammation Arachidonic acid ( 花生四烯酸 ) in the cell membrane turns into prostaglandin ( 前列腺素 ) Arachidonic acid ( 花生四烯酸 ) in the cell membrane turns into prostaglandin ( 前列腺素 ) Gastrin ↑ Growth factors↑ Activate oncogene Too less gastric juice, too much gastrin → Atrophic gastritis → Abnormal cells proliferation massively Too less gastric juice, too much gastrin → Atrophic gastritis → Abnormal cells proliferation massively + Hp exists

Cag A EGFR VEGF Vessels proliferation

After Hp disappears

Diagnosis & Cure Ⅰ. Invasive examination 1.Cell cultivation 2.Urease test 3.Tissue examination Ⅱ. Noninvasive examination 1. Urea breath test 2. Serum examinationUrea breath test Ⅲ. Cure Proton and potassium pump inhibitor amoxicillin, clarithromycin metronidazole.

Conclusion

VacA 的變型 vacA 基因中段 m1 m2 蛋白質訊號段 s1 s1a s1b S1c s2

VacA 基因型之普及率

CagA 白血球釋放 1L-1βTNFα ROS 聚集 更多白血球聚集 更嚴重的發炎反應 COX-2 ↑ Gastrin ↑ Oncogenes↑ Growth factors ↑ 胃酸過少，胃泌素過多，萎縮性胃炎，不正常 細胞大量增殖 胃酸分泌 ↓ ＋

COX-2 PGE2 直接抑制 apoptosis 15d-PGJ2 抑制 pro-apoptoic gene 轉錄 抑制細胞凋亡 與 PPARr 受體結合

IL-8 又發單核球 嗜中 性白血球的趨化作用 還有自由基的聚集. 白血球釋出發炎物質 TNFα (Tumer necrosis factor) 和 IL-1β( 前發炎 激素 )