Major parietal cell antigen in autoimmune gastritis with pernicious anemia is the acid-producing H+,K+-adenosine triphosphatase of the stomach.

Abstract

In autoimmune gastritis antibodies against a membrane-bound parietal cell antigen of previously unknown function are present in the sera of patients. In this study, a vesicular membrane preparation of porcine gastric mucosa cells was found to be a potent antigenic source. This preparation blocked > 90% of antibody binding to a lysate of gastric mucosa cells. The membrane fraction contained H+,K+-ATPase (EC 3.6.136) as the major protein, which in sodium dodecyl sulfate-polyacrylamide gel electrophoresis migrated with a weight of 92 kD.After reduction and alkylation, this component was resolved into two bands of similar staining intensity (92 and 88 kD). Immunoblotting analysis showed that sera of patients recognized antigen with pattern identical to the major protein of the vesicular membranes.Protein A-Sepharose beads preincubated with immunoglobulins of five individual patient (but not control) sera were all found to reduce both the H+,K+-ATPase activity and the amount of parietal cell antigen of a preparation of vesicular membranes solubilized in n-octylglucoside. Taken together, the results of this study indicate that the major parietal cell antigen is identical to the acid-producing enzyme, H+,K+-ATPase, of the parietal cell.

H+,K+-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis

“…Rather, T-cell recognition of porcine H ϩ ,K ϩ -ATPase at the gastric level is specific for patients with gastric autoimmunity and reasonably results from reactivity against T-cell epitopes shared by both human and porcine H ϩ ,K ϩ -ATPase. Previous studies have shown that H ϩ ,K ϩ -ATPase prepared from vesicular membranes isolated from porcine gastric mucosa as a 114-kilodalton protein is specifically recognized by parietal cell autoantibodies present in patients with AIG, [5][6][7][8][9] in some patients with gastritis associated with postpartum thyroiditis, 4 and in a subgroup of H. pylori-infected patients who develop parietal cell autoantibodies and mucosal atrophy of the gastric corpus. 32,33 Because human H ϩ ,K ϩ -ATPase (natural or cloned) was not available, the porcine enzyme that can be purified in large amounts and is at least 95% identical was used.…”

“…2,3 AIG and PCA were found in a proportion of women with postpartum thyroiditis, and examination of biopsy specimens from the gastric corpus of these patients showed moderate corpus atrophy, mucosal infiltration by CD4 T cells and macrophages, and abundant epithelial expression of HLA-DR. 4 In AIG patients, with or without pernicious anemia, H ϩ ,K ϩ -adenosine triphosphatase (ATPase), the proton pump of parietal cells, is the key autoantigen recognized by PCA. [5][6][7][8][9] Gastric H ϩ ,K ϩ -ATPase is also the major autoantigen in experimental autoimmune gastritis (EAIG), an organ-specific autoimmune disease that can be elicited in nonthymectomized animals by immunization with either gastric mucosal extracts or purified gastric H ϩ ,K ϩ -ATPase 10 -15 or by neonatal thymectomy. 16,17 These models of AIG are characterized by an inflammatory infiltrate in the gastric mucosa, subsequent loss of acid-secreting parietal cells and zymogenic cells, and late appearance of circulating autoantibodies directed against the ␣ and ␤ subunits of parietal cell H ϩ ,K ϩ -ATPase.…”

Spontaneous Large-Scale Lymphoid Neogenesis and Balanced Autoimmunity versus Tolerance in the Stomach of H+/K+-ATPase-Reactive TCR Transgenic Mouse

“…Autoimmune gastritis (AIG) is an organ-specific autoimmune disease that occurs in 1-2% of people over 60 years old in Western populations (12)(13)(14). AIG is characterized by the extensive loss of parietal cells in the gastric mucosa (GM) and is associated with pernicious anemia as a consequence of vitamin B 12 deficiency.…”

CD4+CD25+ T Cells Prevent the Development of Organ-Specific Autoimmune Disease by Inhibiting the Differentiation of Autoreactive Effector T Cells

“…It is also one of the few spontaneous models of organ-specific autoimmune disease in which the target Ag, the proton pump of the gastric parietal cell (H/KATPase), has been defined (11,12). In addition, it represents a good animal model for chronic gastritis in man leading to pernicious anemia in which the T and B cell responses in humans also target H/K-ATPase (13)(14)(15). We previously generated TCR-transgenic (TCR-Tg) mice expressing TCRs derived from T cell clones isolated from the gastric lymph node of d3Tx mice in the process of developing AIG (10,16,17).…”