Digestive Diseases and Sciences

, Volume 51, Issue 10, pp 1810–1817 | Cite as

Neuroimmune Link in the Mucosa of Chronic Gastritis with Helicobacter pylori Infection

  • G. Sipos
  • K. Altdorfer
  • É. Pongor
  • L. P. Chen
  • E. Fehér
Original Paper


It is suggested that different neuropeptides regulate gastric mucosal integrity and participate in the development of chronic gastritis. The aim of this study was to examine the roles and changes of immunoreactive (IR) nerves and immunocompetent cells in human gastritis. Immunohistochemical, immunocytochemical, and confocal laser microscopic methods were used. All investigated nerve fibers were found in different quantities in the mucosa of both control and gastritis samples. The number of SP, NPY, and VIP IR nerve fibers increased significantly (P < 0.05) in gastritis. No IR immunocompetent cells (lymphocytes, plasma cells, mast cells) were found in the control, however, some showed NPY (16.8%) and SP (9.4%) immunoreactivity in chronic gastritis. The distance between nerve fibers and immunocompetent cells was 200 nm to 1 μm. In conclusion, the increased number of SP, NPY, and VIP IR nerves and IR immunocytes suggests that they participate in development of neurogenic inflammation, repairing processes of chronic gastritis.


Neuropeptides Gastritis Neuroimmunomodulation Immunohistochemistry 



The authors would like to thank Ms. E. Burka for assisting with the manuscript.


  1. 1.
    Blaser MJ, Parsonnet J (1994) Parasitism by the “slow” bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest 94:4–8PubMedCrossRefGoogle Scholar
  2. 2.
    Zavros Y, Kao JY, Juanita L, Merchant L (2004) Inflammation and cancer. III. Somatostatin and the innate immune system. Am J Physiol Gastrointest Liver Physiol 286:G698–G701PubMedCrossRefGoogle Scholar
  3. 3.
    El-Omar EM, Penman ID, Ardill J, Chittajallu RS, Howie C, McColl KE (1995) Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 109:681–691PubMedCrossRefGoogle Scholar
  4. 4.
    Wood JD (1992) Gastrointestinal neuroimmune interactions. In: Holle GE, Wood JD (eds) Advances in the innervation of the gastrointestinal tract. Elsevier Science, Amsterdam, pp 607–615Google Scholar
  5. 5.
    Berthoud HR (1996) Morphological analysis of vagal input to gastrin releasing peptide and vasoactive intestinal peptide containing neurons in the rat glandular stomach. J Comp Neurol 370:61–70PubMedCrossRefGoogle Scholar
  6. 6.
    Gyires K (2004) Neuropeptides and gastric mucosal homeostasis. Curr Top Med Chem 4:63–73PubMedCrossRefGoogle Scholar
  7. 7.
    Green T, Dockray GJ (1987) Calcitonin gene-related peptide and substance P in afferent to the upper gastrointestinal tract in the rat. Neurosci Lett 76:151–156PubMedCrossRefGoogle Scholar
  8. 8.
    Sternini C, Reeve JRJr, Brecha N (1987) Distribution and characterization of calcitonin gene-related peptide immunreactivity in the digestive system of normal and capsaicin-treated rats. Gastroenterology 93:852–862PubMedGoogle Scholar
  9. 9.
    Levine JD, Clark R, Devor M, Helms C, Moskowitz MA, Basbaum AI (1984) Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–549PubMedCrossRefGoogle Scholar
  10. 10.
    Batbayar B, Somogyi J Zelles T, Fehér E (2003) Immunohistochemical analysis of substance P containing nerve fibers and their contacts with mast cells in the diabetic rat’s tongue. Acta Biol Hung 54:275–283PubMedCrossRefGoogle Scholar
  11. 11.
    Ottaway CA, Stanisz AM (1995) Neural-immune interactions in the intestine: Implications for inflammatory bowel disease. In: Kirsner JB, Shorter RG (eds) Inflammatory bowel disease. Williams and Wilkins, Baltimore, pp 281–300Google Scholar
  12. 12.
    Holzer P, Livingston EH, Saria A, Guth PH (1991) Sensory neurons mediate protective vasodilatation in rat gastric mucosa. Am J Physiol 260:G363–G370PubMedGoogle Scholar
  13. 13.
    Reinshagen M, Patel A, Sottili M, French S, Sternini C, Eysselein VE (1996) Action of sensory neurons in an experimental rat colitis model of injury and repair. Am J Physiol 270:G79–G86PubMedGoogle Scholar
  14. 14.
    Singh LK, Pang X, Alexacos N, Letourneau R, Theoharides TC (1999) Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders. Brain Behav Immun 13:225–239PubMedCrossRefGoogle Scholar
  15. 15.
    Stead RH (1992) Innervation of mucosal immune cells in the gastrointestinal tract. Reg Immunol 4:91–99PubMedGoogle Scholar
  16. 16.
    Stead RH, Perdue MH, Blennerhassett MG, Kakuta Y, Sestini P, Bienenstock J (1990) The innervation of mast cells. In: Freier A (ed) The neuroendocrine-immune network. CRC Press, Boca Raton, FL, pp 19–37Google Scholar
  17. 17.
    Williams RM, Bienenstock J, Stead RH (1995) Mast cells: the neuroimmune connection. In: Marone G (ed) Human basophils and mast cells: biological aspects, Vol 61. Karger, Basel, pp 208–235Google Scholar
  18. 18.
    Fehér E, Kovács Á, Gallatz K, Fehér J (1997) Direct morphological evidence of neuroimmunomodulation in colonic mucosa of patients with Crohn’s disease. Neuroimmunomodulation 4:250–257PubMedGoogle Scholar
  19. 19.
    Zavros Y, Rieder G, Ferguson A, Samuelson IC, Merchant JL (2002) Genetic or chemical hypoclorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology 123:119–133CrossRefGoogle Scholar
  20. 20.
    Befus D (1994) Reciprocity of mast cell-nervous system interactions. In: Tache Y, Wingate DL, Burks TF (eds) Innervation of the gut: pathophysiological implications. CRC Press, Boca Raton, FL, pp 315–329Google Scholar
  21. 21.
    Williams RM, Berhoud HR, Stead RH (1997) Vagal afferent nerve fibers contact mast cells in rat small intestinal mucosa. Neuroimmunomodulation 4:266–270PubMedGoogle Scholar
  22. 22.
    Levite M, Chowers Y (2001) Nerve-driven immunity: neuropeptides regulate cytokine secretion of T cells and intestinal epithelial cells in a direct, powerful and contextual manner [Review]. Ann Oncol 12(Suppl 2):19–25CrossRefGoogle Scholar
  23. 23.
    Mignini F, Streccioni V, Amenta F (2003) Autonomic innervation of immune organs and neuroimmune modulation. Auton Autacoid Pharmacol 23:1–25PubMedCrossRefGoogle Scholar
  24. 24.
    Price AB (1991) The Sydney System: histological division. J Gastroenterol Hepatol 6:209–222PubMedGoogle Scholar
  25. 25.
    Haines KA, Kolasinski SI, Cronstein BN, Reibman J, Gold LI, Weissmann G (1993) Chemoattraction of neutrophils by substance P and transforming growth factor-beta 1 is inadequately explained by current models of lipid remodeling. J Immunol 15:1491–1499Google Scholar
  26. 26.
    Kahler CM, Sitte BA, Reinisch N, Wiedermann CJ (1993) Stimulation of the chemotactic migration of human fibroblasts by substance P. Eur J Pharmacol 249:281–286PubMedCrossRefGoogle Scholar
  27. 27.
    Schratzberger P, Reinisch N, Prodinger WM, Kahler CM, Sitte BA, Bellmann R, Fischer-Colbri R, Winkler H, Wiedermann CJ (1997) Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. J Immunol 158:3895–3901PubMedGoogle Scholar
  28. 28.
    O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin C, Shanahan F (2004) The role of substance P in inflammatory disease. J Cell Physiol 201:167–180PubMedCrossRefGoogle Scholar
  29. 29.
    Lorton D, Bellinger DL, Felten SY, Felten DL (1991) Substance P innervation of spleen in rats: nerve fibers associated with lymphocytes and macrophages in specific compartments in the spleen. Brain Behav Immun 5:29–40PubMedCrossRefGoogle Scholar
  30. 30.
    Reubi JC, Horisberger U, Kappeler A, Laissue JA (1998) Localization of receptors for vasoactive intestinal peptide, somatostatin and substance P in distinct compartments of human lymphoid organs. Blood 92:191–197PubMedGoogle Scholar
  31. 31.
    Pascual DW, Kiyono H, McGhee JR (1994) The enteric nervous and immune systems: interactions for mucosal immunity and inflammation [Review]. Immunomethods 5:56–72PubMedCrossRefGoogle Scholar
  32. 32.
    Martinez C, Delgado M, Pozo D, Leceta J, Calvo JR, Ganea D, Gomariz RP (1998) Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J Leuokoc Biol 63:591–601Google Scholar
  33. 33.
    Ganea D, Delgado M (2002) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity [Review]. Crit Rev Oral Biol Med 3:229–237CrossRefGoogle Scholar
  34. 34.
    Bedoui S, Kawamura N, Straub RH, Pabst R, Yamamura T, von Horsten S (2003) Relevance of neuropeptide Y for the neuroimmune crosstalk [Review]. J Neuroimmunol 134:1–11PubMedCrossRefGoogle Scholar
  35. 35.
    Shanahan F (1994) The intestinal immune system. In: Johnson LR (ed) Physiology of the gastrointestinal tract. Raven Press, New York, pp 643–684Google Scholar
  36. 36.
    Fehér E, Altdorfer K, Bagaméri G, Fehér J (2001) Neuroimmune interactions in experimental colitis. Neuroimmunomodulation 9:247–255PubMedCrossRefGoogle Scholar
  37. 37.
    Tripp RA, Barskey A, Goss L, Anderson LJ (2002) Substance P receptors expression on lymphocytes is associated with immune response to respiratory syncytial virus infection. J Neuroimmunol 129:141–153PubMedCrossRefGoogle Scholar
  38. 38.
    Lai JP, Douglas SD, Ho WZ (1998) Human lymphocytes express substance P and its receptor. J Neuroimmunol 86:80–86PubMedCrossRefGoogle Scholar
  39. 39.
    Martinez C, Delgado M, Abad C, Gomariz RP, Ganea D, Leceta J (1999) Regulation of VIP production and secretion by murine lymphocytes. J Neuroimmunol 93:126–138PubMedCrossRefGoogle Scholar
  40. 40.
    Batbayar B, Nagy G, Kövesi G, Zelles T, Fehér E (2004) Morphological basis of sensory neuropathy and neuroimmunomodulation in minor salivary glands of patients with Sjögren’s syndrome. Arch Oral Sci 49:529–538CrossRefGoogle Scholar
  41. 41.
    Ho WZ, Lai JP, Zhu XH, Uvaydova M, Douglas SD (1997) Human monocytes and macrophages express substance P, neurokinin-1 receptor. J Immunol 159:5654–5660PubMedGoogle Scholar
  42. 42.
    Lai JP, Douglas SD, Zhao M, Ho WZ (1999) Quantification of substance P mRNA in human mononuclear phagocytes and lymphocytes using a mimic-based RT-PCR. J Immunol Methods 230:149–157PubMedCrossRefGoogle Scholar
  43. 43.
    Wang H, Xing L, Li W, Hou L, Guo J, Wang X (2002) Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 130:155–162PubMedCrossRefGoogle Scholar
  44. 44.
    Bracci-Laudiero L, Aloe L, Stenfors C, Hou L, Guo J, Wang X (1996) Nerve growth factor stimulates production of neuropeptide Y in human lymphocytes. Neuroreport 7:485–488PubMedCrossRefGoogle Scholar
  45. 45.
    Amenta F, Bronzetti E, Cantalamessa F, El-Assouad D, Felici L, Ricci A, Tayebati SK (2001) Identification of dopamine plasma membrane and vesicular transporters in human peripheral blood lymphocytes. J Neuroimmunol 117:133–142PubMedCrossRefGoogle Scholar
  46. 46.
    Toyoda M, Makino T, Kagoura M, Morohashi M (2000) Immunolocalization of substance P in human skin mast cells. Arch Dermatol Res 292:418–421PubMedCrossRefGoogle Scholar
  47. 47.
    Holzer P, Holzer-Petsche U (1997) Tachykinins in the gut. Part II. Roles in neural excitation, secretion, and inflammation. Pharmacol Ther 73:219–263PubMedCrossRefGoogle Scholar
  48. 48.
    Gomariz RP, Delgado M, Naranjo JR, Mellström B, Tormo A, Mata F, Leceta J (1993) VIP gene expression in rat thymus and spleen. Brain Behav Immun 7:271–278PubMedCrossRefGoogle Scholar
  49. 49.
    Gomariz RP, Leceta J, Garrido E, Garrido T, Delgado M (1994) Vasoactive intestinal peptide (VIP) mRNA expression in rat T and B lymphocytes. Regul Pept 50:177–184PubMedCrossRefGoogle Scholar
  50. 50.
    Leceta J, Martinez MC, Delgado M, Garrido E, Gomariz RP (1994) Lymphoid cell subpopulations containing vasoactive intestinal peptide in the rat. Peptides 15:791–797PubMedCrossRefGoogle Scholar
  51. 51.
    Bellinger DL, Lorton D, Horn L, Brouxhon S, Felten SY, Felten DL (1997) Vasoactive intestinal polypeptide (VIP) innervation of rat spleen, thymus, and lymph nodes. Peptides 18:1139–1149PubMedCrossRefGoogle Scholar
  52. 52.
    Jurjus SR, More N, Walsh RJ (1998) Distribution of substance P positive cells and nerve fibers in the rat thymus. J Neuroimmunol 90:143–148PubMedCrossRefGoogle Scholar
  53. 53.
    Gomariz RP, Martinez C, Abad C, Leceta J, Delgado M (2001) Immunology of VIP: a review and therapeutical perspectives [Review]. Curr Pharm Des 7:89–111PubMedCrossRefGoogle Scholar
  54. 54.
    Delgado M, Abad C, Martinez C, Juarranz MG, Leceta J, Ganea D, Gomariz RP (2003) PACAP in immunity and inflammation. Ann NY Acad Sci 992:141–115PubMedCrossRefGoogle Scholar
  55. 55.
    Tuncel N, Erkasap M, Sahinturk V, Ak DD, Tuncel M (1998) The protective effect of vasoactive intestinal peptide (VIP) on stress-induced gastric ulceration in rats. Ann NY Acad Sci 865:309–322PubMedCrossRefGoogle Scholar
  56. 56.
    Kang JC, Yeoh KG, Chia HP, Lee HP, Chia YW, Guan R, Yap ID (1995) Chili-protective factor against peptic ulcer? Dig Dis Sci 40:576–579PubMedCrossRefGoogle Scholar
  57. 57.
    Mózsik GY, Rácz I, Szolcsányi J (2005) Gastroprotection induced by capsaicin in human healthy subjects. World J Gastroenterol 11:5180–5184PubMedGoogle Scholar
  58. 58.
    Mózsik GY,Vincze Á, Szolcsányi J (2001) Four responses of capsaicin-sensitive primary afferent neurons to capsaicin and its analog. Gastric acid secretion, gastric mucosal damage and protection. J Gastroenterol Hepatol 16:1093–1097PubMedCrossRefGoogle Scholar
  59. 59.
    Larauche M, Anton PM, Peiro G, Eutamene H, Bueno L, Fioramonti J (2004) Role of capsaicin-sensitive afferent nerves in different models of gastric inflammation in rats. Auton Neurosci 110:89–97PubMedCrossRefGoogle Scholar
  60. 60.
    Frieri M (2003) Neuroimmunology and inflammation: implications for therapy of allergic and autoimmune diseases. Ann Allergy Asthma Immunol 90(Suppl 3):34–40PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science&#x002B;Business Media, Inc. 2006

Authors and Affiliations

  • G. Sipos
    • 1
  • K. Altdorfer
    • 2
  • É. Pongor
    • 2
  • L. P. Chen
    • 2
  • E. Fehér
    • 2
  1. 1.Department of GastroenterologyUzsoki Teaching HospitalBudapestHungary
  2. 2.Department of Anatomy, Histology and EmbryologySemmelweis UniversityBudapestHungary

Personalised recommendations