The Gastric H/K ATPase in the Pathogenesis of Autoimmune Gastritis
Pernicious anaemia is the commonest cause of vitamin B12 deficiency in man affecting ~2% of the population. Autoimmune gastritis is the underlying cause of this disease. The gastritis results in loss of parietal cells that secrete intrinsic factor required for vitamin B12 absorption in the small intestine. The target antigen of these parietal cell antibodies is the gastric H/K ATPase responsible for secretion of HC1. To examine the role of the gastric H/K ATPase in the pathogenesis of autoimmune gastritis, we adopted and established mouse models of autoimmune gastritis. We showed that the gastritis is initiated by the β subunit of the ATPase because transgenic expression of this subunit in the thymus of gastritis-susceptible BALB/c or BALB/cCrSlc mice renders the mice resistant to development of autoimmune gastritis. We showed that immunological tolerance to the β subunit was established by expression of this subunit in the thymus because thymocytes from transgenic mice failed to transfer gastritis to naive recipients. The mouse gastritis is mediated entirely by TH1-type CD4 T cells. We showed that early lesions of gastritis are characterised by influx of CD4 T cells that secrete a mix of TH1 and TH2 cytokines with the exception of IL-4. A single injection of antibodies to interferon γ prevented the development of gastritis. An unresolved question is the nature of the trigger that initiates gastritis in genetically-susceptible mice. Microbial organisms may initiate gastritis by acting as molecular mimics or through by-stander activation following the generation of pro-inflammatory cytokines. We investigated the role of the pro-inflammatory cytokine GM-CSF in the initiation of gastritis by the transgenic production of this cytokine in the stomach. We selected this cytokine because we have previously shown that it is generated in gastritic lesions and because GM-CSF is a potent activator of antigen-presenting cells that links innate to adaptive immunity. We showed that transgenic expression of GM-CSF in the stomach was alone sufficient to initiate gastritis in genetically-susceptible mice. Our studies support the role of pro-inflammatory by-stander activation in the initiation of gastritis.
KeywordsParietal Cell Pernicious Anemia Cobalamin Deficiency Gastric Parietal Cell Autoimmune Gastritis
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