Helicobacter pylori infection pathophysiology
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Person to person transmission is considered to be the most likely route of transmission of Helicobacter pylori. H. pylori is a noninvasive organism. It is found over mucus secreting cells but not in deeper gastric glands. Hence it can only inhabit gastric-type mucus but cannot colonize the esophagus or duodenum. Pathogenesis of H. pylori infection depends on bacterial, host and environmental factors.
- The mode of transmission of H. pylori is poorly understood.
- Person to person transmission is considered to be the most likely route.
- It is almost always acquired during childhood and infection is lifelong if left untreated.
- Helicobacter pylori is usually transmitted via the following routes:
- Via tubes and endoscopes that have been in contact with the gastric mucosa of one individual are used for another patient
- Between patient and staff especially among endoscopists and gastroenterologists
- Fecal-oral route
- Oral-oral route
- Distal adenocarcinoma is the most common gastric adenocarcinoma which is caused by H. pylori.
- The colonization of H. pylori in gastric mucosa depends on the following factors:
- H. pylori primarily colonizes in gastric mucosa but occasionally found at other sites also. The few of the sites include eyes, nasal cavity, gallbladder, peritoneum, and oral cavity.
- The pathogenesis involves four important steps. They are:
For further information on pathogenesis please click here
Factors Associated With Pathogenesis
- H. pylori is a non invasive organism. It is found over mucus secreting cells but not in deeper gastric glands. Hence it can only inhabit gastric-type mucus but cannot colonize the esophagus or duodenum. . The pathogenesis of H. pylori depends up on the following:
|Factors Associated With H. pylori Pathogenesis|
|Flagella||Immune response to H. pylori|
|Hormonal and acid homeostasis changes
|Bacterial Virulence factors
1: Bacterial factors
B. Bacterial enzymes
- Lipase and protease leads to degradation of protective mucous layer of the stomach
- Protease leads to disintegration of the polymeric structure of mucin
- Phospholipase A2 and lipase leads to loss of mucosal surface hydrophobicity, mucus lipid degradation, and lysophospholipid generation
- Lysophospholipids disrupts the phospholipid rich layer at the apical surface of mucous cells
- Gastric acid resistance plays a crucial role in pathogenesis of H.pylori infection.
- Urease is one of the most abundant protein produced by H.pyloi, whose production is regulated by one of the genes associated with gastric acid resistance
- The urease of H.pylori has two subunits, UreA and UreB.
- This enzyme hydrolyzes urea to ammonia and carbon dioxide, which increases the cytoplasmic pH in the micro environment around the organism, hence protects the bacteria from gastric acid
- The H+-gated urea channel(Urel) regulates the urea entry into cytoplasm of H. pylori cell which helps in quick adaptation of organism to acidic environment.
- Ammonia and ammonium chloride inhibit the growth of gastric cells in S phase, leading to gastric mucosal atrophy
C. Bacterial Virulence factors
The cytotoxin-associated gene (Cag) pathogenecity island (PAI) and cytotoxin-associated gene A (cagA)
- Large amounts of the pro-inflammatory cytokine interleukin-8 are expressed in H. pylori strains with CagPaI.
- The protein CagA is encoded by CagA gene and type IV bacterial secretion system (T4SS) is encoded by CagPAI.
- Type IV bacterial secretion apparatus helps in translocation of CagA into host target cells and stimulates epithelial cell pro-inflammatory cytokine expression and gastric inflammation
- CagA undergoes phosphorylation in host target cells
The following are the bacterial virulence factors associated with H. pylori pathogenesis:
- The CagA protein is encoded by CagA gene and is translocated to epithelial cell cytosol through type IV bacterial secretion apparatus.
- It is activated by phosphorylation on tyrosine residues by host scr kinases.
- After phosphorylation, it interacts with SHP-2 and activates MAP kinase signalling leading to abnormal proliferation of gastric epithelial cells.
- The CagA protein also binds to Crk proteins leading to disruption of epithelial cell tight junctions and tissue damage.
- The type and number of CagA tyrosine phosphorylation motifs differ in the individual strains.
- Strains having CagA with more phosphorylation motifs cause atrophy and gastric carcinoma than strains with fewer motifs.
- The IL-8 secretion is independent of tyrosine phosphorylation of CagA but dependent on the region having phosphorylation motifs.
Outer inflammatory protein A (OipA)
- OipA strain is associated with duodenal ulceration and gastric cancer
- This protein is regulated by slipped strand mispairing
Duodenal ulcer promoting gene A (dupA)
Blood group antigen binding adhesion A (BabA)
- BabA2 gene encodes the active form of BabA which binds to fucosylated Le antigens which are expressed on gastric epithelial cells.
- BabA increases the adhesion of H. pylori to epithelial cells which leading to increased delivery of factors associated with inflammation.
- Active form of BabA is associated with increased association of Cag+ strains with gastric cancer and duodenal ulceration.
The RNA polymerase β-subunit (RpoB)
- The RpoBThr is associated with increased secretion of IL-8 from MKN45 cells compared to RpoBAla.
- H. pylori strains possessing RpoBThr is seen in 67.6% of East Asians and hence associated with increased risk of development of more severe gastroduodenal diseases.
The vacuolating cytotoxin (VacA)
- VacA is an exotoxin which is associated with cellular damage rather than pro-inflammatory cytokine release.
- The active forms of VacA are associated with increased risk of gastric carcinoma
2. Host genetic susceptibility
- The stable polymorphisms of several cytokine gens
- Increased expression of IL-1β or tumor necrosis factor-alpha (TNF)α
- The reduced expression of the anti-inflammatory cytokine IL-10 due to single nucleotide polymorphism
A.The immune response to H.Pylori
The innate immune response
- H. pylori colonization of the gastric mucosa is associated with innate host defense mechanisms leading to the expression of pro-inflammatory and anti-bacterial factors.The expression of these factors results in gastritis.
- The severity of the H. pylori disease and gastric carcinogenesis is associated with the innate immune response.
- The innate immune mechanisms are dependent on the Nod1, which is a pattern recognition receptors (PRR) stimulated by cag+ strains.
- Defensins are the anti-microbial peptides which are secreted as a response to H. pylori infection. Elevated levels of human β defensin 2 (hBD2) and the neutrophil-derived alpha defensins are detected in gastric juice of infected patients.
- The infected gastric epithelial cells have increased expression of hBD2, hBD3, angiogenin, adrenomedullin, and the human cationic antimicrobial peptide 18 (LL-37).
- Due to high secretion of cytokines and chemokines by the gastric epithelial cells, there is increased migration of granulocytes, lymphocytes and monocytes leading to severe inflammatory pathology.
- The H. pylori after phagocytosis survive inside the phagosome and all phagosomes fuse to become megasomes. This provides a protected intracellular cavity in the macrophage, contributing to the persistence of infection.
The acquired immune response
- H. pylori stimulates the production of mucosal and systemic IgA and IgG antibodies which induces local inflammation and damage by cross reacting with the parietal cell H+,K+-ATPase and antigens on gastric epithelial cells.
- The T-helper 1 (Th1) response in the gastric mucosa dominates the T-cell response to H. pylori. The Th1 cells release type 1 cytokines (IFNγ) which activate macrophages resulting in secretion of pro-inflammatory factors (TNFα, IL-12 and IL-18) and increase bactericidal activity compared to those activated by Th2 cytokines. The severity of gastritis depends on the number of IFNγ-secreting cells in the infected gastric mucosa.
- H. pylori suppress immune and inflammatory responses by eliciting Treg (T-cell regulatory) responses and thus maintain chronic colonization. They also suppress human memory T-cells in response to H. pylori antigens.
B. Hormonal changes and acid homeostasis changes
Somatostatin and gastrin changes
- The inflammatory mediators produced due to H. pylori infection, including nitric oxide suppress somatostatin release. The infection is also associated with reduced numbers of somatostatin-producing D cells in the stomach.
- The gastrin production from G cells is increased due to direct stimulatory action of cytokines and suppression of somatostatin.
- Hypergastrinemia stimulates MAP kinase which results in up-regulation of the cox-2 gene which is potentially has potentially pro-oncogenic effect. It may also leads to gastric atrophy by up-regulation of the Reg protein.
- Hypergastrinemia leads to excess acid production leading to dyspepsia.
3. Environmental cofactors
The environmental co-factors associated with H. pylori are:
The microscopic pathology depends on the the following stages:
Acute H.pylori infection
- Most of the initial H. pylori colonization occur during childhood but new infections may occur in adults occasionally.
- Associated with transient profound gastric hypochlorhydria
Chronic H.pylori infection
- Chronic antral predominant inflammation:
- Associated with increased stimulated acid production leading to duodenal ulceration
- Chronic corpus-predominant or pangastritis
- Epithelial degeneration
- Neutrophil infiltration
- predominantly lymphocyte, monocyte and/ or plasma cell infiltration in the superficial lamina propria
- Glandular atrophy
- Intestinal metaplasia
- Lymphoid tissue aggregates
Pathogenesis of H.pylori Infection
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