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 Barry Marshall drank the solution with germs caused gastric inflammation cured with antibiotic Koch's postulates proof 1.Proved H. pylori the pathogen 2.Invented C 13 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 Factors Virulence Factors Urease VacA CagA HOST CELL Adhesin Injection Flagellin Secret TFSS

Urease Mucus H2OH2O NH 3 CO 2 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

Leb BabA 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-LexSabA Vigorous inflammantory response H. pylori might have gain local advantage In the prepared of escaping of intimate contact with lymphocyte or other defensive cells.

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 TFSS

SH2(N-SH2 C-SH2 ) protein tyrosine phosphatase

IL-8 TFSS NF-kB IL-8(interlukin-8) Neutrophil 、 Monocyte TNFα 、 IL-1 pH increased NF-κB

VacA (Vacuolating cytotoxin A) -Discovery: 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

IL-12 INF-γ B cell T H 1 activate little B cells INF-γ INF-γ ： 1.Increase antigen presenting of macrophage 2.Attract more macrophage to the epithelial cells ↓ inflammation IL-2 T cell→Tc Macrophage DC= dendritic cell

Dendritic cell IL-10 IL-12 T H 2 cell B cell T H 2 cell release IL-4 ↓ B cell proliferation Stimulate T H 2 cell Inhibit T H 1 cell IL-4 INF-γ Chronic gastritis Macrophage

Acute gastritisChronic gastritis H.Pylori Non-DC-SIGN DC-SIGN EnvironmentTH1 cell TH1&TH2 cell in balance Macrophagemorefewer B celllittleMuch Persistent colonization of Hp in presence of mild gastritis High level of inflammation Comparison between acute and chronic gastritis

Gastric Cancer Benign gastric ulcer

Cox2 cyclooxygenase-2 Cox2 Arachidonic acid 花生四烯酸 Arachidonic acid 花生四烯酸 PG PGE2 15d-PGj2 PPAR-γ Apoptosis EGFR VEGF Angiogenesis G-protein coupled receptor G-protein coupled receptor BCL2↑ in the cell membrane Protein kinase cascade Activate transcription of anti-apoptotic genes Activate 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 ) VEGF Angiogenesis NO

Protein kinase cascade Cox2 mRNA transcription↑ Cox2↑ K-Ras Mutated K-Ras Oncogene Cannot repair p53 Mutated p53

Diagnoses Invasive testing ： Histological examination Culture P.C.R. Rapid urease test Non-invasive testing ： Serology test Scatological examination C 13 -urea breath test

NH 2 C 13 ONH 2 NH 3 ＋ H 2 C 13 O 3 H 2 C 13 O 3 → H 2 O + C 13 O 2 Urease C 13 Urea 13

Cures Triple 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~

1. Vacuolation BACK

2. Apoptosis BACK

3.Increase paracellular epithelial permeability BACK

4.T-lyphocyte Immunosuppression BACK

Type four secretion system (TFSS) BACK