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The discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease. 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. Content. Discoverers Helicobacter pylori Virulence factors Immunoreactions Gastritis
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The discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease 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
Content Discoverers Helicobacter pylori Virulence factors Immunoreactions Gastritis Gastric cancer Diagnosis & Cure Summary
Drs. Barry Marshall and Robin Warren • Successfully cultivated H. pylori • Showed below Robin Warren • Proved H. pylori the pathogen • Invented C13 urea breath test Barry Marshall
Helicobacter Pylori • Gram negative • Spiral shaped • Microaerophilic bacterium • 2~4 um • Inhabit in stomach and duodenum
Epidemiology 90% 80% 20% • 50% affection rate • socio-economic status<race • Oralaffection • Reduce obese Ashma GERD(Gastroesophageal Reflux Disease)
Virulence Factors Pathogenic Factors Flagellin Urease Adhesin VacA Secret TFSS HOST CELL Injection CagA
Mucus Urease PH<4 4<PH<8.2 H2O CO2 Urea Urease NH3 Neutralize gastric acid 空泡變性 Epithelial cells
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
Persistence infection and chronic inflammation(gastritis) BabA Leb s-Lex SabA H. pylori use BabA for recognition of Leb H. pylori triggers the host to retailor mucosal glycosylation patterns to up-regulate s-Lex 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
NF-κB TFSS IL-8(interlukin-8) Neutrophil、Monocyte NF-kB TNFα、IL-1 pH increased IL-8
VacA(Vacuolating cytotoxin A) -Discovery: 1980 -Subunits: p37&p58 -Oligomer complex
3. Increase paracellular epithelial permeability 2. Apoptosis 1.Vacuolation 4.T-lyphocyte Immunosuppression
Acute gastritis Chronic gastritis
Acute gastritis INF-γ: 1.Increase antigen presenting of macrophage 2.Attract more macrophage to the epithelial cells ↓ inflammation Macrophage INF-γ B cell DC= dendritic cell TH1 activate little B cells IL-2 T cell→Tc INF-γ IL-12
Chronic gastritis INF-γ IL-4 Macrophage Dendritic cell TH2 cell release IL-4 ↓ B cell proliferation B cell TH2 cell IL-10 Stimulate TH2 cell Inhibit TH1 cell IL-12
Comparison between acute and chronic gastritis Persistent colonization of Hp in presence of mild gastritis High level of inflammation
Gastric Cancer Benign gastric ulcer
Cox2cyclooxygenase-2 Cox2 PG Arachidonic acid 花生四烯酸 PGE2 15d-PGj2 in the cell membrane PPAR-γ G-protein coupled receptor EGFR Activate transcription of anti-apoptotic genes Protein kinase cascade VEGF BCL2↑ Apoptosis Angiogenesis
ROS NO Angiogenesis VEGF Reactive oxygen species(自由基) Tissue DNA damage Mutation activation of host signaling pathways (carcinogen) Angiogenesis(血管新生)
Oncogene K-Ras p53 Mutated K-Ras Mutated p53 Protein kinase cascade Cox2 mRNA transcription↑ Cannot repair Cox2↑
Diagnoses Invasive testing: Histological examination Culture P.C.R. Rapid urease test Non-invasive testing: Serology test Scatological examination C13-urea breath test
13 C13 Urea 13 13 Urease • NH2C13ONH2NH3 + H2C13O3 • H2C13O3→ H2O+C13O2
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!!!!!!!!