Helicobacter pylori infection pathophysiology: Difference between revisions

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*Increased expression of  IL-1β or tumor necrosis factor (TNF)α
*Increased expression of  IL-1β or tumor necrosis factor (TNF)α
*The reduced expression of the anti-inflammatory cytokine IL-10 due to single necleotide polymorphism
*The reduced expression of the anti-inflammatory cytokine IL-10 due to single necleotide polymorphism
====The immune response to H.Pylori====


===='''Environmental cofactors'''====
===='''Environmental cofactors'''====

Revision as of 15:59, 4 January 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Overview

Helicobacter pylori (H. pylori) is a bacterium that lives on the lining of the stomach. Although we used to think that spicy food, acid, and stress were the major causes of ulcers, we now know that nine out of ten ulcers are caused by H. pylori. Medicines that reduce stomach acid may make you feel better, but your ulcer may come back. Here's the good news: Since most ulcers are caused by this bacterial infection, they can be cured with the right antibiotics.

Pathophysiology

  • The mode of transmission of H.pylori is poorly understood.[1][2][3]
  • 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.[4]
  • Helicobacter pylori is usually transmitted via the following routes:
  • Iatrogenic
  • 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
  • Fecal contamination of water and food may be the source of infection especially in developing countries[4]
  • Oral-oral route
  • Via saliva especially in developed countries[4]

Pathogenesis

  • The pathogenesis of H.pylori depends up on the following:[5]

Bacterial factors

  • Bacterial enzymes[6]
  • Lipase and protease
  • 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 lysoophospholipid generation[7][8]
  • Lysophospholipids disrupts the phospholipid rich layer at the apical surface of mucous cells
  • Urease
  • The urease of H.pylori has two sub units, UreA and UreB[9][10]
  • This enzyme produces ammonia, which increases the pH in the microenvironment around the organism, hence protects the bacteria from acid
  • Ammonia and ammonium chloride inhibit the growth of gastric cells in S phase, leading to gastric mucosal atrophy[11]
  • 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 CagPal.
  • 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
1: CagA
  • 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.[12][13]
  • After phosphorylation, it interacts with SHP-2 and activates MAP kinase signalling leading to abnormal proliferation of gastric epithelial cells.
  • It 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.
  • [14][15][16]
  • The IL-8 secretion is independent of tyrosine phosphorylation of CagA but dependent on the region having phosphorylation motifs.
2: Outer inflammatory protein A (OipA)
  • OipA strain is associated with duodenal ulceration and gastric cancer[17][18]
  • This protein is regulated by slipped strand mispairing[19]
3: Duodenal ulcer promoting gene A (dupA)
  • This gene is associated with duodenal ulceration but appeared to protect from gastric cancer in patients from columbia, Japan and South Korea.[20]
4: 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.[21]
  • 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.[22]
5: 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.[23]
6: The vacuolating cytotoxin (VacA)
  • VacA is associated with cellular damage rather than pro-inflammatory cytokine release.
  • The active forms of VacA are associated with increased risk of gastric carcinoma


Host genetic susceptibility

The risk of gastric carcinoma increases due to :[24][25]

  • The stable polymorphisms of several cytokine gens
  • Increased expression of IL-1β or tumor necrosis factor (TNF)α
  • The reduced expression of the anti-inflammatory cytokine IL-10 due to single necleotide polymorphism

The immune response to H.Pylori

Environmental cofactors

  • Age at infection
  • Degree of crowding

Bacterial Virulence factors

Based on duration of disease, H.pylori infection is classified into acute and chronic

Acute H.pylori infection

  • Most of the initial H.pylori colonization occur during childhood but new infections may occur in adults occasionally.[26]
  • Associated with transient profound gastric hypochlorhydria
  • Histopathogenesis
  • Heavy neutrophilic infiltration
  • Gradual infiltration of other inflammatory cells, especially lymphocytes

Chronic H.pylori infection

  • Chronic antral predominant inflammation:
  • Associated with increased stimulated acid production leading to duodenal ulceration
  • Chronic corpus-predominant or pan-gastritis
  • Associated with reduced acid production
  • Predisposes to gastric ulceration and gastric adenocarcinoma
  • Histopathogenesis
  • predominantly lymphocytic infiltration







Following transmission, the H.pylori can directly injure gastric epithelial cells by the secretion of enzymes and by the elaboration of toxins.[6][27]


The pathophysiology of helicobacter pylori infection

  • Helicobacter pylori (H. pylori) is a spiral-shaped bacterium that is found in the gastric mucous layer or adherent to the epithelial lining of the stomach. H. pylori causes more than 90% of duodenal ulcers and up to 80% of gastric ulcers.
  • Before 1982, when this bacterium was discovered, spicy food, acid, stress, and lifestyle were considered the major causes of ulcers.
  • The majority of patients were given long-term medications, such as H2 blockers, and more recently, proton pump inhibitors, without a chance for permanent cure. These medications relieve ulcer-related symptoms, heal gastric mucosal inflammation, and may heal the ulcer, but they do not treat the infection.
  • When acid suppression is removed, the majority of ulcers, particularly those caused by H. pylori, recur.
  • Since we now know that most ulcers are caused by H. pylori, appropriate antibiotic regimens can successfully eradicate the infection in most patients, with complete resolution of mucosal inflammation and a minimal chance for recurrence of ulcers.

Peptic Ulcer Disease from H. Pylori

A peptic ulcer is a sore or hole in the lining of the stomach or duodenum (the first part of the small intestine). People of any age can get an ulcer and women are affected just as often as men. Over 25 million Americans will suffer from an ulcer at some point during their lifetime. The good news is that most ulcers are caused by an infection with the bacterium, Helicobacter pylori , and can be cured in about two weeks with antibiotics.

  • Most ulcers are caused by an infection, not spicy food, acid or stress.
  • The most common ulcer symptom is burning pain in the stomach.
  • Your doctor can test you for H. pylori infection.
  • Antibiotics are the new cure for ulcers.
  • Eliminating H. pylori infections with antibiotics means that your ulcer can be cured for good.

References

  1. ↑ Brown LM (2000). "Helicobacter pylori: epidemiology and routes of transmission". Epidemiol Rev. 22 (2): 283–97. PMID 11218379.
  2. ↑ Cave DR (1997). "How is Helicobacter pylori transmitted?". Gastroenterology. 113 (6 Suppl): S9–14. PMID 9394753.
  3. ↑ Transmission http://www.who.int/bulletin/archives/79(5)455.pdf (2001) Accessed on December 27, 2016
  4. ↑ 4.0 4.1 4.2 Das JC, Paul N (2007). "Epidemiology and pathophysiology of Helicobacter pylori infection in children". Indian J Pediatr. 74 (3): 287–90. PMID 17401270.
  5. ↑ Atherton JC (2006). "The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases". Annu Rev Pathol. 1: 63–96. doi:10.1146/annurev.pathol.1.110304.100125. PMID 18039108.
  6. ↑ 6.0 6.1 Smoot DT (1997). "How does Helicobacter pylori cause mucosal damage? Direct mechanisms". Gastroenterology. 113 (6 Suppl): S31–4, discussion S50. PMID 9394757.
  7. ↑ Berstad K, Sjödahl R, Berstad A (1994). "Phospholipase A2 activity in gastric juice from patients with active and H. pylori-eradicated healed duodenal ulcer". Aliment Pharmacol Ther. 8 (2): 175–80. PMID 8038348.
  8. ↑ Mauch F, Bode G, Ditschuneit H, Malfertheiner P (1993). "Demonstration of a phospholipid-rich zone in the human gastric epithelium damaged by Helicobacter pylori". Gastroenterology. 105 (6): 1698–704. PMID 8253346.
  9. ↑ Smoot DT, Mobley HL, Chippendale GR, Lewison JF, Resau JH (1990). "Helicobacter pylori urease activity is toxic to human gastric epithelial cells". Infect Immun. 58 (6): 1992–4. PMC 258755. PMID 2341188.
  10. ↑ Micots I, Augeron C, Laboisse CL, Muzeau F, Mégraud F (1993). "Mucin exocytosis: a major target for Helicobacter pylori". J Clin Pathol. 46 (3): 241–5. PMC 501178. PMID 8463418.
  11. ↑ Matsui T, Matsukawa Y, Sakai T, Nakamura K, Aoike A, Kawai K (1995). "Effect of ammonia on cell-cycle progression of human gastric cancer cells". Eur J Gastroenterol Hepatol. 7 Suppl 1: S79–81. PMID 8574744.
  12. ↑ Selbach M, Moese S, Hauck CR, Meyer TF, Backert S (2002). "Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo". J Biol Chem. 277 (9): 6775–8. doi:10.1074/jbc.C100754200. PMID 11788577.
  13. ↑ Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A (2002). "c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs". Mol Microbiol. 43 (4): 971–80. PMID 11929545.
  14. ↑ Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC (2004). "Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori". Gastroenterology. 127 (2): 514–23. PMID 15300584.
  15. ↑ Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y; et al. (2002). "Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan". J Infect Dis. 186 (11): 1621–30. doi:10.1086/345374. PMID 12447739.
  16. ↑ Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR (1998). "Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases". J Clin Microbiol. 36 (8): 2258–63. PMC 105028. PMID 9666002.
  17. ↑ Yamaoka Y, Kikuchi S, el-Zimaity HM, Gutierrez O, Osato MS, Graham DY (2002). "Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production". Gastroenterology. 123 (2): 414–24. PMID 12145793.
  18. ↑ Yamaoka Y, Ojo O, Fujimoto S, Odenbreit S, Haas R, Gutierrez O; et al. (2006). "Helicobacter pylori outer membrane proteins and gastroduodenal disease". Gut. 55 (6): 775–81. doi:10.1136/gut.2005.083014. PMC 1856239. PMID 16322107.
  19. ↑ Yamaoka Y, Kwon DH, Graham DY (2000). "A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori". Proc Natl Acad Sci U S A. 97 (13): 7533–8. doi:10.1073/pnas.130079797. PMC 16580. PMID 10852959.
  20. ↑ Zhang Z, Zheng Q, Chen X, Xiao S, Liu W, Lu H (2008). "The Helicobacter pylori duodenal ulcer promoting gene, dupA in China". BMC Gastroenterol. 8: 49. doi:10.1186/1471-230X-8-49. PMC 2584642. PMID 18950522.
  21. ↑ Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET; et al. (1998). "Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging". Science. 279 (5349): 373–7. PMID 9430586.
  22. ↑ Gerhard M, Lehn N, Neumayer N, Borén T, Rad R, Schepp W; et al. (1999). "Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin". Proc Natl Acad Sci U S A. 96 (22): 12778–83. PMC 23096. PMID 10535999.
  23. ↑ Lee KH, Cho MJ, Yamaoka Y, Graham DY, Yun YJ, Woo SY; et al. (2004). "Alanine-threonine polymorphism of Helicobacter pylori RpoB is correlated with differential induction of interleukin-8 in MKN45 cells". J Clin Microbiol. 42 (8): 3518–24. doi:10.1128/JCM.42.8.3518-3524.2004. PMC 497570. PMID 15297492.
  24. ↑ El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA; et al. (2000). "Interleukin-1 polymorphisms associated with increased risk of gastric cancer". Nature. 404 (6776): 398–402. doi:10.1038/35006081. PMID 10746728.
  25. ↑ Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S; et al. (2003). "A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma". Gastroenterology. 125 (2): 364–71. PMID 12891537.
  26. ↑ Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.
  27. ↑ Jhala NC, Siegal GP, Klemm K, Atkinson BF, Jhala DN (2003). "Infiltration of Helicobacter pylori in the gastric mucosa". Am J Clin Pathol. 119 (1): 101–7. doi:10.1309/YDTX-KE06-XHTH-FNP2. PMID 12520704.

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