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. 1997 Sep;92(1):91–98. doi: 10.1046/j.1365-2567.1997.00302.x

Immunization with gastric H+/K(+)-ATPase induces a reversible autoimmune gastritis.

K J Scarff 1, J M Pettitt 1, I R Van Driel 1, P A Gleeson 1, B H Toh 1
PMCID: PMC1363986  PMID: 9370929

Abstract

The gastric H+/K(+)-ATPase has been implicated as a major autoantigen in pernicious anaemia in humans and in thymectomy-induced autoimmune gastritis in mice. Here we have shown that autoimmune gastritis can be generated by direct immunization of non-thymectomized BALB/c mice with mouse gastric H+/K(+)-ATPase in complete Freund's adjuvant. The gastritis was characterized by infiltration of the gastric submucosa and mucosa with macrophages, CD4+ and CD8+ T cells, and B cells and by circulating autoantibodies to the H+/K(+)-ATPase. The mononuclear infiltrate within the gastric mucosa was accompanied by loss of parietal and zymogenic cells and accumulation of small immature epithelial cells. Splenocytes from gastritic mice adoptively transferred gastritis to naive recipients. Cessation of immunization resulted in decrease in autoantibody titre and regeneration of parietal and zymogenic cells. The results directly confirm that the gastric H+/K(+)-ATPase is the causative autoantigen in the genesis of autoimmune gastritis. Recovery of the lesion following cessation of immunization suggests that homeostatic mechanisms can reverse a destructive autoimmune process.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderuccio F., Toh B. H., Tan S. S., Gleeson P. A., van Driel I. R. An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus. J Exp Med. 1993 Aug 1;178(2):419–426. doi: 10.1084/jem.178.2.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrada J. A., Rose N. R., Andrada E. C. Experimental autoimmune gastritis in the Rhesus monkey. Clin Exp Immunol. 1969 Mar;4(3):293–310. [PMC free article] [PubMed] [Google Scholar]
  3. Asano M., Toda M., Sakaguchi N., Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996 Aug 1;184(2):387–396. doi: 10.1084/jem.184.2.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barrett S. P., Toh B. H., Alderuccio F., van Driel I. R., Gleeson P. A. Organ-specific autoimmunity induced by adult thymectomy and cyclophosphamide-induced lymphopenia. Eur J Immunol. 1995 Jan;25(1):238–244. doi: 10.1002/eji.1830250139. [DOI] [PubMed] [Google Scholar]
  5. Beinborn M., Giebel J., Linck M., Cetin Y., Schwenk M., Sewing K. F. Isolation, identification and quantitative evaluation of specific cell types from the mammalian gastric mucosa. Cell Tissue Res. 1993 Nov;274(2):229–240. doi: 10.1007/BF00318742. [DOI] [PubMed] [Google Scholar]
  6. Bonomo A., Kehn P. J., Shevach E. M. Post-thymectomy autoimmunity: abnormal T-cell homeostasis. Immunol Today. 1995 Feb;16(2):61–67. doi: 10.1016/0167-5699(95)80089-1. [DOI] [PubMed] [Google Scholar]
  7. Callaghan J. M., Khan M. A., Alderuccio F., van Driel I. R., Gleeson P. A., Toh B. H. Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis. Autoimmunity. 1993;16(4):289–295. doi: 10.3109/08916939309014648. [DOI] [PubMed] [Google Scholar]
  8. Callaghan J. M., Toh B. H., Simpson R. J., Baldwin G. S., Gleeson P. A. Rapid purification of the gastric H+/K(+)-ATPase complex by tomato-lectin affinity chromatography. Biochem J. 1992 Apr 1;283(Pt 1):63–68. doi: 10.1042/bj2830063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chuang J. S., Callaghan J. M., Gleeson P. A., Toh B. H. Diagnostic ELISA for parietal cell autoantibody using tomato lectin-purified gastric H+/K(+)-ATPase (proton pump). Autoimmunity. 1992;12(1):1–7. doi: 10.3109/08916939209146123. [DOI] [PubMed] [Google Scholar]
  10. FIXA B., VEJBORA O., KOMARKOVA O., LANGR F., PARIZEK J. ON IMMUNOLOGICALLY INDUCED GASTRIC ATROPHY IN DOGS. Gastroenterologia. 1964;102:331–338. doi: 10.1159/000202270. [DOI] [PubMed] [Google Scholar]
  11. Fixa B., Thiele H. G., Komárková O., Nozicka Z. Gastric autoantibodies and cell-mediated immunity in pernicious anaemia--a comparative study. Scand J Gastroenterol. 1972;7(3):237–240. doi: 10.3109/00365527209181159. [DOI] [PubMed] [Google Scholar]
  12. Gleeson P. A., Toh B. H. Molecular targets in pernicious anaemia. Immunol Today. 1991 Jul;12(7):233–238. doi: 10.1016/0167-5699(91)90036-S. [DOI] [PubMed] [Google Scholar]
  13. Gleeson P. A., Toh B. H., van Driel I. R. Organ-specific autoimmunity induced by lymphopenia. Immunol Rev. 1996 Feb;149:97–125. doi: 10.1111/j.1600-065x.1996.tb00901.x. [DOI] [PubMed] [Google Scholar]
  14. HENNES A. R., SEVELIUS H., LEWELLYN T., JOEL W., WOODS A. H., WOLF S. Atrophic gastritis in dogs. Production by intradermal injection of gastric juice in Freund's adjuvant. Arch Pathol. 1962 Apr;73:281–287. [PubMed] [Google Scholar]
  15. Jones C. M., Callaghan J. M., Gleeson P. A., Mori Y., Masuda T., Toh B. H. The parietal cell autoantigens recognized in neonatal thymectomy-induced murine gastritis are the alpha and beta subunits of the gastric proton pump [corrected]. Gastroenterology. 1991 Aug;101(2):287–294. doi: 10.1016/0016-5085(91)90002-3. [DOI] [PubMed] [Google Scholar]
  16. Jones C. M., Toh B. H., Pettitt J. M., Martinelli T. M., Humphris D. C., Callaghan J. M., Goldkorn I., Mu F. T., Gleeson P. A. Monoclonal antibodies specific for the core protein of the beta-subunit of the gastric proton pump (H+/K+ ATPase). An autoantigen targetted in pernicious anaemia. Eur J Biochem. 1991 Apr 10;197(1):49–59. doi: 10.1111/j.1432-1033.1991.tb15881.x. [DOI] [PubMed] [Google Scholar]
  17. Kontani K., Taguchi O., Takahashi T. Involvement of the H+/K(+)-ATPase alpha subunit as a major antigenic protein in autoimmune gastritis induced by neonatal thymectomy in mice. Clin Exp Immunol. 1992 Jul;89(1):63–67. doi: 10.1111/j.1365-2249.1992.tb06878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krohn K. J., Finlayson N. D. Interrelations of humoral and cellular immune responses in experimental canine gastritis. Clin Exp Immunol. 1973 Jun;14(2):237–245. [PMC free article] [PubMed] [Google Scholar]
  19. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  20. MAXWELL A. THE ALCIAN DYES APLIED TO GASTRIC MUCOSA. Stain Technol. 1963 Sep;38:286–287. [PubMed] [Google Scholar]
  21. Martinelli T. M., van Driel I. R., Alderuccio F., Gleeson P. A., Toh B. H. Analysis of mononuclear cell infiltrate and cytokine production in murine autoimmune gastritis. Gastroenterology. 1996 Jun;110(6):1791–1802. doi: 10.1053/gast.1996.v110.pm8964405. [DOI] [PubMed] [Google Scholar]
  22. Mori Y., Fukuma K., Adachi Y., Shigeta K., Kannagi R., Tanaka H., Sakai M., Kuribayashi K., Uchino H., Masuda T. Parietal cell autoantigens involved in neonatal thymectomy-induced murine autoimmune gastritis. Studies using monoclonal autoantibodies. Gastroenterology. 1989 Aug;97(2):364–375. doi: 10.1016/0016-5085(89)90072-3. [DOI] [PubMed] [Google Scholar]
  23. Nishio A., Hosono M., Watanabe Y., Sakai M., Okuma M., Masuda T. A conserved epitope on H+,K(+)-adenosine triphosphatase of parietal cells discerned by a murine gastritogenic T-cell clone. Gastroenterology. 1994 Nov;107(5):1408–1414. doi: 10.1016/0016-5085(94)90543-6. [DOI] [PubMed] [Google Scholar]
  24. SALTHOUSE T. N. A quantitative histochemical method for estimating phospholipids. Nature. 1962 Jul 14;195:187–188. doi: 10.1038/195187a0. [DOI] [PubMed] [Google Scholar]
  25. Sakaguchi S., Fukuma K., Kuribayashi K., Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985 Jan 1;161(1):72–87. doi: 10.1084/jem.161.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995 Aug 1;155(3):1151–1164. [PubMed] [Google Scholar]
  27. Smith H., Sakamoto Y., Kasai K., Tung K. S. Effector and regulatory cells in autoimmune oophoritis elicited by neonatal thymectomy. J Immunol. 1991 Nov 1;147(9):2928–2933. [PubMed] [Google Scholar]
  28. Strickland R. G., Mackay I. R. A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis. 1973 May;18(5):426–440. doi: 10.1007/BF01071995. [DOI] [PubMed] [Google Scholar]
  29. Taguchi O., Takahashi T. Administration of anti-interleukin-2 receptor alpha antibody in vivo induces localized autoimmune disease. Eur J Immunol. 1996 Jul;26(7):1608–1612. doi: 10.1002/eji.1830260730. [DOI] [PubMed] [Google Scholar]
  30. Thean E. T., Toh B. H. Production and characterization of murine monoclonal antibody to human alpha-lactalbumin. Immunol Cell Biol. 1989 Feb;67(Pt 1):41–48. doi: 10.1038/icb.1989.5. [DOI] [PubMed] [Google Scholar]
  31. Toh B. H., Gleeson P. A., Simpson R. J., Moritz R. L., Callaghan J. M., Goldkorn I., Jones C. M., Martinelli T. M., Mu F. T., Humphris D. C. The 60- to 90-kDa parietal cell autoantigen associated with autoimmune gastritis is a beta subunit of the gastric H+/K(+)-ATPase (proton pump). Proc Natl Acad Sci U S A. 1990 Aug;87(16):6418–6422. doi: 10.1073/pnas.87.16.6418. [DOI] [PMC free article] [PubMed] [Google Scholar]

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