ReviewThe causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis
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H+/K+ ATPase autoantibody isotype is IgG1 (Th2 associated), not IgG2a (Th1 associated) (F. Alderuccio et al., unpublished).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
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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.
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