The Nobel Prize in Physiology or Medicine 2005

Class A Group 4王彥昇、何長軒、吳庭瑜、呂庭毅、卓韋儒、林欣聖、林庭蔚、張剛瑋

The discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease

Content

Discoverers Helicobacter pylori Virulence factors Immunoreactions Gastritis Gastric cancer Diagnosis & Cure Summary

Drs. Barry Marshall and Robin Warren

Robin Warren

Barry Marshall

1. Proved H. pylori the pathogen

2. Invented C13 urea breath test

1. Successfully cultivated H. pylori

2. Showed below

Helicobacter Pylori

Gram negative Spiral shaped Microaerophilic bacterium 2~4 um Inhabit in stomach and

duodenum

Epidemiology

20%

80%

90%

50% affection rate socio-economic

status<race Oral affection Reduce obese

Ashma

GERD(Gastroesophageal

Reflux Disease)

Pathogenic FactorsVirulence Factors

Urease

VacA

CagA

HOST CELL

Adhesin

Injection

Flagellin

Secret

TFSS

Urease

Mucus

H2O

NH3

CO2

Urea

Neutralize gastric

acid

Epithelial cells

空泡變性

PH<4 4<PH<8.2

Urease

Adherence of H. pylori• Adhesin

- BabA(histo-blood group antigen binding adhesion)

- SabA (sialic acidbinding adhesion)• LPS(lipopolysaccharide)

-- Lex(Lewis x)

-- Ley(Lewis y)• Lewis blood group antigen• Related ABO antigens

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LebBabA

Persistence infection and chronic inflammation(gastritis)

H. pylori triggers the host to retailor mucosal glycosylation patterns to up-regulate s-Lex

H. pylori use BabA for recognition of Leb

s-Lex SabA

Vigorous inflammantory response

H. pylori might have gain local advantageIn the prepared of escaping of intimate contact with lymphocyte or other defensivecells.

cagA (cytotoxin associated gene A) Cag PAI (Cag pathogenicity island )

a. cagA( exists in 60%~70% H. pylori)

b. TFSS

Translate to protein CagA (cytotoxin associated antigen A )

a. a 120–145-kDa protein

cag PAI

TFSSTFSS

SH2(N-SH2 C-SH2 )

protein tyrosine phosphatase

IL-8IL-8

TFSSTFSS

NF-kBNF-kB

IL-8(interlukin-8) IL-8(interlukin-8)

Neutrophil 、 Monocyte

Neutrophil 、 Monocyte

TNFα 、 IL-1 TNFα 、 IL-1

pH increasedpH increased

NF-κBNF-κB

VacA (Vacuolating cytotoxin A)

-Discovery: 1980-Subunits: p37&p58-Oligomer complex

1.Vacuolation

3. Increase paracellular epithelial permeability

2. Apoptosis

4.T-lyphocyte Immunosuppression

H. pylori induced gastric ulcer

Chronic gastritisAcute gastritis

Acute gastritis

IL-12IL-12

INF-γINF-γ

B cellB cell

TTHH1 activate little B cells1 activate little B cells

INF-γINF-γ

INF-γ：1.Increase antigen presenting of macrophage2.Attract more macrophage to the epithelial cells

↓inflammation

IL-2IL-2

T cell→TcT cell→Tc

MacrophageMacrophage

DC= dendritic cellDC= dendritic cell

Dendritic cellDendritic cell

IL-10IL-10

IL-12IL-12

TTHH2 cell2 cell

B cellB cell

TTHH2 cell release IL-42 cell release IL-4

↓ ↓

B cell proliferationB cell proliferation

Stimulate TStimulate THH2 2

cellcellInhibit TInhibit THH1 cell1 cell

IL-4IL-4INF-γINF-γ

Chronic gastritis

MacrophageMacrophage

Acute gastritis Chronic gastritis

H.Pylori Non-DC-SIGN DC-SIGN

Environment TH1 cellTH1&TH2 cell

in balance

Macrophage more fewer

B cell little Much

Persistent colonization of Hp in presence of mild gastritis

High level of inflammation

Comparison between acute and chronic gastritis

Gastric Cancer

Benign gastric ulcer

Cox2cyclooxygenase-2

Cox2Cox2

Arachidonic acid花生四烯酸

Arachidonic acid花生四烯酸

PGPG

PGE2PGE2 15d-PGj215d-PGj2

PPAR-γPPAR-γ

ApoptosisApoptosis

EGFREGFR

VEGFVEGF

AngiogenesisAngiogenesis

G-protein coupled receptor

G-protein coupled receptor

BCL2↑BCL2↑

in the cell membranein the cell membrane

Protein kinase cascade

Protein kinase cascade

Activate transcription of anti-apoptotic genesActivate transcription

of anti-apoptotic genes

ROS

Reactive oxygen species( 自由基 ) Tissue DNA damage Mutation activation of host signaling

pathways (carcinogen) Angiogenesis( 血管新生 )

VEGFVEGF AngiogenesisAngiogenesis

NONO

Protein kinase cascadeProtein kinase cascade

Cox2 mRNA transcription↑Cox2 mRNA transcription↑

Cox2↑Cox2↑

K-RasK-Ras

Mutated K-Ras

Mutated K-Ras

Oncogene

Cannot repair

Cannot repair

p53p53

Mutated p53Mutated p53

DiagnosesInvasive testing ：

Histological examination Culture P.C.R. Rapid urease test

Non-invasive testing ： Serology test Scatological examination C13-urea breath test

NH2C13ONH2 　 　 NH3 　＋　 H2C13O3

　　　　H2C13O3 　→ H2O + C13O2

Urease

C13 Urea

13

13

13

CuresTriple therapy 三合一療法 & 飲食控制

1.Antibiotics + bismuth subsalicylate( 鉍鹽 )

2.Antibiotics + proton pump inhibitors

Curability 80%~90%. And it’s permanent!Nobel prize get!

Summary

Helicobacter pylori Virulence factors Immunoreactions Gastritis Gastric cancer Nobel prize get!!!

Thanks to this pioneering discovery, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be permanently cured.

Gastric cancer

→Nobel prize get!!!!!!!!

Thanks for your listening~