• Ali Ibrahim Ali Al-ezzy Department of pathology,College of Veterinary medicine,Diyala University,Iraq


Objectives: To determine the role of Bcl2 and p53 gene expression in the pathogenesis of antral-predominant non-atrophic gastritis (APNG) according
to Helicobacter pylori (HP) cytotoxin-associated gene A (CagA) status.
Methods: Multiple antral biopsies were taken from 78 patients for rapid urease test, histopathology, Bcl2 and P53 immunohistochemistry and HP
CagA in situ hybridization.
Results: CagA was detected in 74.35% cases. There was no significant difference in Bcl2 expression among CagA+ and CagA− APNG cases. Significant
differences in polymorphonuclear neutrophils (PMNs) and lymphocytes grades were detected among CagA+ and CagA− APNG cases. There was no
significant correlation among patients’ age, inflammatory infiltrates, Bcl2, p53 expression. CagA has positive correlation with p53 (p=0.001), PMNs
grade (p=0.027), lymphocytes grade (p=0.003), inflammation intensity (p=0.006), and inflammation activity (p=0.007). Bcl2 has no significant
correlation with p53, CagA, PMNs, and lymphocytes indexes. P53 expression has significant correlation with PMNs and lymphocyte grades (p=0.000),
inflammation intensity (p=0.003), and inflammation activity (p=0.002). PMNs grade has positive correlation with lymphocyte grade, inflammation
intensity, and activity (p=0.000). Lymphocyte grade has a significant correlation with inflammation intensity and activity (p=0.000). Inflammation
intensity has a significant correlation with inflammation activity (p=0.000).
Conclusions: CagA cytotoxin has direct effect on P53 gene and indirect effect on Bcl2 gene expression in APNG cases. Bcl2 and P53 expression do
not get affected by patient’s age and gender. PMNs grade, lymphocytes grade, inflammation intensity, and inflammation activity affected directly by
P53 and CagA cytotoxin expression and indirectly by Bcl2 expression. The balance of P53-Bcl2 pathways play a vital role in pathogenesis of HP and
CagA-induced APNG.
Keywords: Antral-predominant non-atrophic gastritis, Bcl2, p53, Helicobacter pylori, Cytotoxin-associated gene A.


1. Al-Ezzy AI. Evaluation of clinicopathological and risk factors for nonmalignant H. Pylori associated gastroduodenal disorders in iraqi patients. Open Access Maced. J Med Sci 2015;3(4):645-54.
2. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol 2005;36(3):228-33.
3. Watari J, Chen N, Amenta PS, Fukui H, Oshima T, Tomita T, Miwa H, Lim KJ, Das KM. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol 2014;20(18):5461-73.
4. Paniagua GL, Monroy E, Rodríguez R, Arroniz S, Rodríguez C, Cortés JL, Camacho A, Negrete E, Vaca S. Frequency of vacA, cagA and babA2 virulence markers in Helicobacter pylori strains isolated from Mexican patients with chronic gastritis. Ann Clin Microbiol Antimicrob 2009;8(1):14.
5. Müller A, Oertli M, Arnold IC. H. Pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection. Cell Commun Signal 2011;9(1):25.
6. Al-Ezzy AI. Molecular and immunopathological role of gastric versus lymphocytes interleukin 8 gene expression in H. Pylori induced fas-fasl apoptotic pathway in gastroduodenal ulcer in Iraqi patients. J Biol, Agric Healthc 2015;5(5):141-53.
7. Kim SS, Ruiz VE, Carroll JD, Moss SF. Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett 2011 28;305(2):228-38.
8. Gucin Z, Akmak T, Bayyurt N, Salih B. Helicobacter pylori infection and relationship with gastric epithelial cell proliferation and apoptosis. Turk Med Sci 2013;43(5):739-46.
9. Shiotani A, Iishi H, Ishiguro S, Tatsuta M, Nakae Y, Merchant JL. Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: Increase of cell proliferation in paramalignant lesions. J Gastroenterol 2005;40(4):337-44.
10. Targa A, Cesar A, Cury P, Silva A. Apoptosis in different gastric lesions and gastric cancer: Relationship with Helicobacter pylori, overexpression of p53 and aneuploidy. Genet Mol Res 2007;6(3):554-65.
11. Wei J, O’Brien D, Vilgelm A, Piazuelo MB, Correa P, Washington MK, et al. Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family. Gastroenterology 2008;134(5):1412-23.
12. Wei JN, Vilgelm A, Zaika E, Ogden SR, Romero-Gallo J, Piazuelo MB, et al. Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 2010;139(4):1333-43.
13. Bimczok D, Smythies LE, Waites KB, Grams JM, Stahl RD, Mannon PJ, et al. Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immunol 2013;190(12):6626-34.
14. Al-Ezzy AI. Immunopathological role of FAS-FASL apoptotic pathway in H. Pylori CagA positive associated chronic atrophic gastritis in Iraqi patients. J Biol Agric Healthc 2014;4(23):67-4.
15. Stolte M, Meining A. The updated Sydney system: Classification and grading of gastritis as the basis of diagnosis and treatment. Can J Gastroenterol 2001;15(9):591.
16. Forbes B, Sahm D, Weissfeld A, editors. Bailey and Scott Diagnostic Microbiology. St. Louis, MO: Mosby; 2002.
17. Immunohistochemistry Detection Kit LSAB2 System-HRP. Available from:
18. Xia HH, Zhang GS, Talley NJ, Wong BC, Yang Y, Henwood C, et al. Topographic association of gastric epithelial expression of Ki-67, Bax, and Bcl-2 with antralization in the gastric incisura, body, and fundus. Am J Gastroenterol 2002;97(12):3023-31.
19. Teh M, Tan KB, Seet BL, Yeoh KG. Study of p53 immunostaining in the gastric epithelium of cagA positive and cagA negative Helicobacter pylori gastritis. Cancer 2002;95(3):499-505.
20. In situ Hybridization Detection System. Available from:
21. Camorlinga-Ponce M, Romo C, Gonzalez-Valencia G, Munoz O, Torres J. Topographical localisation of cagA positive and cagA negative Helicobacter pylori strains in the gastric mucosa; An in situ hybridisation study. J Clin Pathol 2004;57(8):822-8.
22. Vilaichone RK, Mahachai V, Shiota S, Uchida T, Ratanachu-ek T, Tshering L, et al. Extremely high prevalence of Helicobacter pylori infection in Bhutan. World J Gastroenterol 2013;19(18):2806.
23. Al-Ezzy AI. In situ nick end labeling as a molecular immunopathological indicator for the severity of DNA fragmentationand gastroduodenal tissue damage among H. Pylori Cag A positive patients. Indian J Sci Technol 2016;9(2):1-11.
24. Sasidharan S, Ghayethry B, Ravichandran M, Latha LY, Lachumy SJ, Leng KM, et al. Prevalence of Helicobacter pylori infection among patients referred for endoscopy: Gender and ethnic differences in Kedah, Malaysia. Asian Pac J Trop Dis 2012;2(1):55-9.
25. Al-Ezzy AIA. Evaluation of endoscopy based H. Pylori diagnostic techniques in Iraqi patients with upper gastrointestinal disorders. IJST 2016;9(22):1-10.
26. Morales-Fuentes G, Zarate-Osorno A, Quinez-Urrego E, Antonio-Manrique M, Martnez-Garcأa C, Figueroa-Barojas P, et al. p53 expression in the gastric mucosa of patients infected with Helicobacter pylori. Rev Gastroenterol Mex 2013;78(1):12-20.
27. Krashias G, Bashiardes S, Potamitou A, Potamitis GS, Christodoulou C. Prevalence of Helicobacter pylori cagA and vacA genes in cypriot patients. J Infect Dev Ctries 2013, 7(9):642-50.
28. Secka O, Antonio M, Berg DE, Tapgun M, Bottomley C, Thomas V, et al. Mixed infection with cagA positive and cagA negative strains of Helicobacter pylori lowers disease burden in the Gambia. PLoS One 2011;6(11):e27954.
29. Lidia C, Taulescu M, Dan LD. Helicobacter pylori in Romania: Epidemiology, diagnosis and treatment. Helicobacter pylori: A Worldwide Perspective 2014. Oak Park, IL USA: Science Publishers; 2014. p. 183-201.
30. Lee SY. Helicobacter pylori in South-Eastern Asia. Helicobacter pylori: A Worldwide Perspective 2014. Bentham Science; 2014. p. 92-129.
31. Rokkas T. Helicobacter pylori in Greece: Epidemiology, Diagnosis, and Treatment. Helicobacter pylori: A Worldwide Perspective 2014. Bentham Science; 2014. p. 202-15.
32. Xu XQ, Wang ZH, Liao JX, Chen XY, Liu WZ, Xiao SD, Lu H. Predictive value of neutrophil infiltration as a marker of Helicobacter pylori infection. World J Gastroenterol 2012;18(36):5101.
33. Rolig AS, Cech C, Ahler E, Carter JE, Ottemann KM. The degree of Helicobacter pylori-triggered inflammation is manipulated by preinfection host microbiota. Infect Immun 2013;81(5):1382-9.
34. Pity IS, Baizeed AM. Identification of Helicobacter pylori in gastric biopsies of patients with chronic gastritis: Histopathological and immunohistochemical study. Duhok Med J 2011;5(1):69-77.
35. Al-Ezzy AI. Immunomodulatory effect of H. Pylori Cag A genotype and gastric hormones on gastric versus inflammatory cells fas gene expression in Iraqi patients with gastroduodenal disorders. Open Access Maced J Med Sci 2016;4(3):364-73.
36. Varbanova M, Malfertheiner P. Bacterial load and degree of gastric mucosal inflammation in Helicobacter pylori infection. Dig Dis 2011;29(6):592-9.
37. Nai GA, Parizi AC, Barbosa RL. Association between Helicobacter pylori concentration and the combining frequency of histopathological findings in gastric biopsies specimens. Arq Gastroenterol 2007;44(3):240-3.
38. Aryana K, Reza KM, Zakavi SR, Sadeghian MH, Akbari H. Association of Helicobacter pylori infection with the Lewis and ABO blood groups in dyspeptic patients. Niger Med J 2013;54(3):196-9.
39. Argent RH, Thomas RJ, Letley DP, Rittig MG, Hardie KR, Atherton JC. Functional association between the Helicobacter pylori virulence factors VacA and CagA. J Med Microbiol 2008;57(2):145-50.
40. Aspholm M. Adaptation of Helicobacter Pylori Adherence Properties in Promotion of Host Tropism and Inflammatory Disease. Sweden: UMEÃ University; 2004.
41. Hofner P, Gyulai Z, Kiss ZF, Tiszai A, Tiszlavicz L, Toth G, et al. Genetic polymorphisms of NOD1 and IL8, but not polymorphisms of TLR4 genes, are associated with Helicobacter pylori induced duodenal
Asian J Pharm Clin Res, Vol 10, Issue 3, 2017, 142-148
ulcer and gastritis. Helicobacter 2007;12(2):124-31.
42. Ihan A, Pinchuk IV, Beswick EJ. Inflammation, immunity, and vaccines for Helicobacter pylori infection. Helicobacter 2012;17(1):16-21.
43. Hofner P, Gyulai Z, Kiss ZF, Tiszai A, Tiszlavicz L, Toth G, et al. Genetic polymorphisms of NOD1 and IL†8, but not polymorphisms of TLR4 genes, are associated with Helicobacter pylori induced duodenal ulcer and gastritis. Helicobacter 2007;12(2):124-31.
44. Andrei V, Gudkov KV, Elena AK. Inflammation and p53: A tale of two stresses. Gene Cancer 2011;2(4):503-16.
45. Deng X, Gao F, Flagg T, Anderson J, May WS. Bcl2’s flexible loop domain regulates p53 binding and survival. Mol Cell Biol 2006;26(12):4421-34.
46. Olivares D, Gisbert JP, Pajares JM. Helicobacter pylori infection and gastric mucosal epithelial cell apoptosis. Rev Esp Enferm Dig 2005;97(7):505-20.
47. Mimuro H, Suzuki T, Nagai S, Rieder G, Suzuki M, Nagai T, et al. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe 2007;2(4):250-63.
48. Twaij AD. Invasive and Non Invasive Methods for the Detection of H. pylori With Some Molecular Aspects of its Pathogenesis (Bax mRNA by I.S. H. and Bcl-2 by I.H.C.). Ph.D. Thesis. College of Medicine, Al-Nahrain University; 2006.
49. Liu HF, Liu WW, Wang GA, Teng XC. Effect of Helicobacter pylori infection on bax protein expression in patients with gastric precancerous lesions. World J Gastroenterol 2005;11(37):5899-901.
50. Hasson HA, Hassan HA, Hassan BA, Ali TW. Bcl-2 expression in CagA strain H. Pylori gastritis (Immunohistochemical and in situ hybridization study). Iraqi Postgrad Med J 2012;11(1):71-5.
51. Bartchewsky JW, Martini MR, Squassoni AC, Alvarez MC, Ladeira MS, Salvatore DM, et al. Effects of Helicobacter pylori infection on the expressions of bax and Bcl-2 in patients with chronic gastritis and gastric cancer. Dig Dis Sci 2010;55(1):111-16.
52. Chu SH, Lim JW, Kim DG, Lee ES, Kim KH, Kim H. Down-regulation of Bcl-2 is mediated by NF-κB activation in Helicobacter pylori-induced apoptosis of gastric epithelial cells. Scand J Gastroenterol 2011;46(2):148-55.
53. Al-Ezzy AI. Molecular and immunopathological role of nuclear factor k b detected by in situ hybridization in pathogenesis of chronic atrophic gastritis in Iraqi patients. Int J Adv Res 2014;2(1):67-78.
54. Pham KT, Fischer W. Helicobacter pylori utilizes DNA shuffling to modulate the gastric inflammatory response. Future Microbiol 2013;8(7):835-8.
55. Witkowska M, Smolewski P. Helicobacter pylori infection, chronic inflammation, and genomic transformations in gastric MALT lymphoma. Mediators Inflamm 2013;2013:1-8.
56. Lynch DA, Mapstone NP, Clarke AM, Jackson P, Moayyedi P, Dixon MF. Correlation between epithelial cell proliferation and histological grading in gastric mucosa. J Clin Pathol 1999;52(5):367-71.
57. Kohda K, Tanaka K, Aiba Y, Yasuda M, Miwa T, Koga Y. Role of apoptosis induced in Helicobacter pylori infection in the development of duodenal ulcer. Gut 1999;44(4):456-62.
58. Rokkas T, Ladas S, Liatsos C, Petridou E, Papatheodorou G, Theocharis S, et al. Relationship of H. Pylori cag A status to gastric cell proliferation and apoptosis. Dig Dis Sci 1999;44(3):487-93.
59. Suzuki H, Suzuki M, Mori M, Kitahora T, Yokoyama H, Miura S, et al. Augmented levels of gastric mucosal leucocyte activation by infection with cagA gene positive Helicobacter pylori. J Gastroenterology Hepatol 1998;13(3):294-300.
60. Robinson K, Argent RH, Atherton JC. The inflammatory and immune response to Helicobacter pylori infection. Best Pract Res Clin Gastroenterol 2007;21(2):237-59.
268 Views | 305 Downloads
How to Cite
Original Article(s)