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

ContentsContents 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 LaureatesAbout the Laureates--- before they met--- before they met

Barry J. MarshallBarry J. Marshall

1951 1981

1979

J. Robin WarrenJ. Robin Warren

1937 1968 1981

1979

After they metAfter they met---heading toward ---heading toward the Nobel prizethe Nobel prize

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

UreaseUrease

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

VacA pathways

ApoptosisApoptosis

Tight junctionTight junction

VacuolationVacuolation

Apoptosis

VacuolationVacuolationH+ V-ATPase

Oligomerization

Cl- Channel

ApoptosisApoptosis

Tight junctionTight junction

Inhibit T cellactivation

Acute gastritis Chronic gastritis

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)

TFSSTFSS

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

Cag ACag A

EGFREGFR

VEGFVEGF

Vessels proliferation

Vessels proliferation

After Hp disappears

常見

罕有

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.

Conclusion