Review
The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis

https://doi.org/10.1016/S0167-5699(00)01653-4Get rights and content

Abstract

The gastric H+/K+ ATPase is the causative autoantigen recognized by CD4+ T cells that mediate autoimmune gastritis. Pathogenic CD4+ T cells are regulated by CD25+CD4+ T cells. Here, it is proposed that waves of activation and migration of antigen presenting cells and CD4+ T cells to and from the target organ and draining lymph node result in tissue damage.

Section snippets

Mouse models of EAG

A classification of mouse models of EAG into two groups based upon whether or not the mice are lymphopenic is shown in Box 1. (Lymphopenic models of EAG have been reviewed elsewhere3.) Irrespective of induction method, EAG is similar to human gastritis in that it is characterized by a chronic inflammatory infiltrate in the gastric mucosa accompanied by loss of gastric parietal and zymogenic cells (Fig. 1a). Like human gastritis, gastritic mice develop parietal cell autoantibodies (Fig. 1b) to

Genetic susceptibility

Genetic susceptibility of BALB/c mice to EAG is not linked to the major histocompatibility complex (MHC) because H-2 identical DBA mice are resistant. Mapping of susceptibility genes has identified two loci on distil chromosome 4, designated Gasa1 and Gasa2 (Ref. 6). While these loci contain candidate genes that encode members of the tumour necrosis factor receptor (TNFR) family, EAG susceptibility might be due to as yet unidentified genes mapping to this region. Gasa1 and Gasa2 co-localize

Immunopathology

The earliest lesions of EAG induced by neonatal thymectomy, observed at four weeks post-thymectomy are characterized by macrophages and CD4 T cells, accompanied by striking production of MHC class II antigens in epithelial cells of the gastric mucosa. Advanced lesions, observed at 10–12 weeks post-thymectomy are characterized by influx of B cells that form follicular-like aggregates. CD8 T-cell numbers appear unchanged7. Infiltrating mononuclear cells secrete a mix of Th1 and Th2 type

Autoantibodies to gastric H+/K+ ATPase

Association of autoantibodies to gastric H+/K+ ATPase with gastritis supports a combined Th1 and Th2 T-cell response to the gastric autoantigen – consistent with the mix of Th1 and Th2 cytokines and abundant follicular-like B-cell aggregates in the gastric lesion. The predominant H+/K+ ATPase autoantibody isotype is IgG1 (Th2 associated), not IgG2a (Th1 associated) (F. Alderuccio et al., unpublished). The antibodies may be produced in the stomach and/or in the draining gastric lymph node.

The causative gastric H+/K+ ATPase autoantigen

The development of EAG after immunization with murine gastric H+/K+ ATPase suggests that the causative autoantigen is the ATPase. As the enzyme comprises an α and a β subunit, which subunit is responsible for disease initiation? This question was addressed by experiments in which either the α or the β subunit of the enzyme was ectopically expressed in murine thymus under the control of mouse MHC class II I-E promoter10, 11. This promoter was selected with the expectation that it would drive

Pathogenic CD4+ T cells

Mouse EAG induced by neonatal thymectomy is mediated by T cells and not by autoantibodies because the disease can be transferred adoptively by T-cell enriched populations and not by antibodies. Pathogenic T cells belong to the CD4+ and not the CD8+ T-cell subset because gastritis can be abrogated by neutralizing antibodies to CD4+ but not by neutralizing antibodies to CD8 (Ref. 19). CD4+ T cells belong to the Th1 subset as EAG induced by neonatal thymectomy can be prevented by a single

Regulatory CD4+ T cells

CD25+ depletion experiments described above suggest that naı̈ve CD4+ T cells also contain a population of regulatory CD4+CD25+ T cells that suppress pathogenic CD4+CD25 T cells. Transfer experiments have indeed shown that this population can prevent autoimmunity induced by neonatal thymectomy, or by adoptive transfer of CD4+CD25 T cells or cloned gastric H+/K+ ATPase-specific effector T cells into T-cell-deficient mice. These observations suggest that CD4+CD25+ T cells cannot only prevent the

Mechanisms of gastric epithelial cell death

What are the mechanisms of parietal and zymogenic cell loss from the gastric mucosa in a disease mediated solely by CD4+ T cells? One mechanism for depletion of parietal and zymogenic cells from the gastric mucosa appears to be failure of differentiation of an expanded immature cell population in the stomach4. However, this does not exclude a direct damaging effect of infiltrating CD4+ T cells on gastric cells. Fas and the TNF receptor are candidate molecules that can mediate gastric

Conclusions and perspectives

Significant progress in understanding the molecular and immunological basis of autoimmune gastritis has been made recently. Two genetic loci, Gasa1 and Gasa2, on chromosome 4 confer EAG susceptibility in BALB/c/CrSlc mice. This region is littered with genes of immunological interest. Mutations in candidate genes in this region will probably allow identification of the genetic component(s) of EAG susceptibility.

Identification of the gastric H+/K+ ATPase as the causative autoantigen and of CD4+ T

Unlinked list

40, 41, 42, 43, 44, 45, 46, 47, 48, 49

Acknowledgements

J.W.S. and F.A. receive salary support from the National Health and Medical Research Council of Australia. Research in the authors’ laboratory was supported by Monash University Research Grants, Alfred Hospital Trusts, and the National Health and Medical Research Council of Australia.

References (50)

  • D. Claeys

    Neonatal injection of native proton pump antigens induces autoimmune gastritis in mice

    Gastroenterology

    (1997)
  • F. Alderuccio et al.

    Spontaneous autoimmune gastritis in C3H/He mice: a new mouse model for gastric autoimmunity

    Am. J. Pathol.

    (1998)
  • B.H. Toh

    Pernicious anaemia

    New Engl. J. Med.

    (1997)
  • P.A. Gleeson

    Organ-specific autoimmunity induced by lymphopenia

    Immunol. Rev.

    (1996)
  • L.M. Judd

    Autoimmune gastritis results in disruption of gastric epithelial cell development

    Am. J. Physiol.

    (1999)
  • K.J. Scarff

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

    Immunology

    (1997)
  • P.A. Silvera

    A major linkage region on distal chromosome 4 confers susceptibility to mouse autoimmune gastritis

    J. Immunol.

    (1999)
  • E. Suri-Payer

    CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells

    J. Immunol.

    (1998)
  • F. Alderuccio

    An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus

    J. Exp. Med.

    (1993)
  • F. Alderuccio

    Expression of the gastric H/K ATPase α-subunit in the thymus may explain the dominant role of the β-subunit in the pathogenesis of autoimmune gastritis

    Autoimmunity

    (1997)
  • S.P. Barrett

    Organ-specific autoimmunity induced by adult thymectomy and cyclosphamide-induced lymphopenia

    Eur. J. Immunol.

    (1995)
  • H.D. de Silva

    Identification of a gastritogenic epitope of the H/K ATPase β-subunit

    Immunology

    (1999)
  • F. Alderuccio

    Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice

    Int. Immunol.

    (2000)
  • E. Suri-Payer

    Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells

    Eur. J. Immunol.

    (1999)
  • R. Tisch

    Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice

    Nature

    (1993)
  • Cited by (91)

    • Helicobacter pylori infection and autoimmune diseases; Is there an association with systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis and autoimmune pancreatitis? A systematic review and meta-analysis study

      2021, Journal of Microbiology, Immunology and Infection
      Citation Excerpt :

      In their study of patients with autoimmune gastritis and corpus mucosal atrophy, Venerito et al. (2016) showed common biomarkers such as gastrin-17, the same level of pepsinogen I and II, antibodies against cagA, partial cells, and intrinsic factor.77 Toh et al. (2000) showed that molecular mimicry exists between the auto-reactive antibody against the H +/K + ATPase pump and H. pylori.105 According to the literature, various Lewis antigens (Lex, Ley and Lex/y) are expressed in gastric epithelium, leukocytes, and endothelial cells.

    • Chronic atrophic gastritis: Natural history, diagnosis and therapeutic management. A position paper by the Italian Society of Hospital Gastroenterologists and Digestive Endoscopists [AIGO], the Italian Society of Digestive Endoscopy [SIED], the Italian Society of Gastroenterology [SIGE], and the Italian Society of Internal Medicine [SIMI]

      2019, Digestive and Liver Disease
      Citation Excerpt :

      Autoimmune gastritis is commonly perceived as a distinct form of chronic gastritis with atrophy being restricted to the corpus mucosa, albeit the detailed mechanisms leading to parietal cell destruction have not been fully elucidated. The H+/K+-ATPase protein was identified as the “target” antigen of autoimmune antibodies possibly triggering the autoimmune response, ultimately leading to loss of parietal cells and functional impairment of the oxyntic mucosa [16–18]. Most frequently, the positivity against APCA is considered a diagnostic hallmark for autoimmune CAG [19], but strict diagnostic criteria for autoimmune CAG are still missing [2].

    View all citing articles on Scopus
    View full text