The 2005 Nobel Prize The 2005 Nobel Prize Helicobacter pylori Helicobacter pylori 64 陳陳陳 62 陳陳陳 80 陳陳陳 91 陳陳陳 60 陳陳陳 75 陳陳陳 71 陳陳陳 63 陳陳陳 59 陳陳陳 陳陳陳陳 : 陳陳陳
The 2005 Nobel PrizeThe 2005 Nobel Prize
Helicobacter pyloriHelicobacter 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
Barry J. MarshallBarry J. Marshall
1951 1981
1979
J. Robin WarrenJ. Robin Warren
1937 1968 1981
1979
1981 Campylobacter-like organisms, CLO 1982 tissue culture & animal model 1984 human model
1989 Helicobacter pylori 2005 Nobel prize
1981 1984 2005 1982 1989
Helicobacter pylori about 3 μm in length
and 0.5 μm 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 proteinsVacA & 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.Adhesion2.TFSS系統
Urease1.使 Hp能在胃部生存2.尿素檢驗法 - 胃是否有Hp
Virulence factorVirulence 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)
FlagellinFlagellin The principal flagellum substituent
Switch between multiple flagellin genes
Activity & Toxicity
AdhesinAdhesin
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
OligomerDouble layer。 12-14
Single layer。 6-7
Acute gastritis
Microphage
Dendritic cell
IL-12
Release IL-12 Release IL-12 (Interleukin(Interleukin細胞間白素細胞間白素 ))→ → activate Tactivate THH1 cells1 cells
Positive Positive feedbackfeedback
INF- γ
Release Release INF(Interferon)-γINF(Interferon)-γ→ → attract more attract more macrophages to macrophages to the infected the infected epithelial cellsepithelial cells→ → inflammationinflammation
Release IL-2 Release IL-2 → activate T→ activate TCC
Activate B cell Activate B cell (little)(little)
B cell
Dendritic cell
IL-10
IL-12
Release IL-12Release IL-12→ → activate Tactivate THH1 cells1 cells
Chronic gastritis
Release IL-10Release IL-10→ → activate Tactivate THH2 cells2 cells→ → inactivate Tinactivate THH1 cells1 cells
INF- γ
IL-4
B cell
Microphage
Release INF-γRelease INF-γ→ → attract more attract more macrophages to macrophages to the infected the infected epithelial cellsepithelial cells→ → inflammationinflammation
Release IL-4Release IL-4→ → activate activate more B cellsmore B cells
ComparisonAcute Chronic
Activation of B cells little much
Species of TH cells TH1 cells TH1 cells 、 TH2 cells
IL-10 released by TH2 cells will inactivate TH1 cells→ By contrast, TH1 cells in chronic gastritis are less→ Reduce the level of inflammation
Inflammatory level high low
CagA(cytotoxin associated gene A)CagA(cytotoxin associated gene A)
an H. pylori virulence factor 11 a 120–145-kDa protein exists in 60%~70% H. pylori. CAG PATHOGENICITY ISLAND (PAI) (PAI) 22 cagA-positive and cagA-negative strains. 3 3 TYPE IV SECRETION SYSTEM(TFSS)(TFSS)
CagA pathways
SH2 protein tyrosine phosphatase 2 (SHP-2)
SH2 : src homology 2 domainsPTP : protein tyrosine
phosphatase
IL-8 assembles monocytes, neutrophils and ROS
Leukocytes secrete a. IL-1β ---proinflammatory cytokinesb. TNFα ---Tumer necrosis factor
Cag ACag A
Gastric epithelial cells
Gastric epithelial cells
IL-8IL-8
ROS aggregation
ROS aggregation
White blood cells aggregation
White blood cells aggregation
Affect cell physiolgy
Affect cell physiolgy
More white blood cells
aggregation
More white blood cells
aggregation
Chronic gastritisChronic gastritis
White blood cells release
cytokines
White blood cells release
cytokinesIL-1βIL-1β
Secrete gastric juice↓
Secrete gastric juice↓
TNFαTNFα
COX-2↑COX-2↑
More serious inflammationMore 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 ↑Gastrin ↑
Growth factors↑Growth factors↑
Activate oncogeneActivate 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 existsHp exists
Diagnosis & Cure Ⅰ. Invasive examination 1.Cell cultivation 2.Urease test 3.Tissue
examination Ⅱ. Noninvasive examination 1. Urea breath test 2. Serum examination Ⅲ. Cure Proton and potassium pump inhibitor
amoxicillin, clarithromycin
metronidazole.