The participation of complement in the parietal cell antigen–antibody reaction in pernicious anaemia and atrophic gastritis

Indirect evidence suggests that the parietal cell antibody circulating in the serum of pernicious anaemia patients is a complement fixing antibody. In this work, we have presented direct evidence using an immunofluorescent technique, that the antigen–antibody union occurring in the gastric mucosa between this antibody and the parietal cell antigen binds complement (C'). We have further adduced data to indicate that serum C' activity was decreased in more than one-third of our patients with pernicious anaemia and in one-fourth of those with advanced atrophic gastritis. Eighty-five per cent of the patients with lowered serum C' had parietal cell antibody in the serum and some of them also had intrinsic factor antibody.

These findings support the concept of the autoimmune mechanism in the development of the gastric atrophic lesion in a proportion of patients with pernicious anaemia and atrophic gastritis. This mechanism includes the participation of complement in the antigen–antibody reaction at the parietal cell level.

     

HL-A3 and HL-A7 in pernicious anaemia and autoimmune atrophic gastritis.

Increased frequencies of HL-A7 and the HL-A3,7 haplotype have been demonstrated in pernicious anaemia. There was no significant increase in any HL-A specificity in autoimmune atrophic gastritis. In the whole series of patients with either pernicious anaemia or atrophic gastritis there was a significant increase in the frequency of HL-A3. No association has been found between any HL-A specificity and an increased incidence of either serum gastric parietal cell or intrinsic factor antibody compared with the overall incidence in pernicious anaemia, atrophic gastritis or in the whole series.     

Spontaneous Autoimmune Gastritis in C3H/He Mice : A New Mouse Model for Gastric Autoimmunity

Autoimmune gastritis is the underlying pathological lesion of pernicious anemia in humans. The lesion is characterized by a chronic inflammatory infiltrate in the gastric mucosa with loss of parietal and zymogenic cells. It is associated with circulating autoantibodies to the gastric H/K-ATPase, the enzyme responsible for acidification of gastric juice. Experimental models of autoimmune gastritis have previously been produced in mice after a variety of manipulations, including thymectomy. Here we report for the first time a spontaneous mouse model of autoimmune gastritis in C3H/He mice. The spontaneous gastritis is also accompanied by circulating autoantibodies to the gastric H/K-ATPase. The spontaneous mouse model should be useful for studies directed toward the immunopathogenesis and treatment of autoimmune gastritis.     

Histamine in gastric carcinoid tumors: Immunocytochemical evidence

Gastric carcinoid tumors and nontumorous corpus mucosa from 4 patients suffering from chronic atrophic gastritis associated with pernicious anemia were characterized histochemically, with special reference to the cellular localization of histamine. Tissue sections were also examined for argentaffinity using the Masson technique, for argyrophilia using the Grimelius and Sevier-Munger techniques, and for chromogranin A and serotonin immunoreactivities. The majority of the tumor cells showed the staining characteristics of enterochromaffinlike cells: That is, they exhibited the argyrophil reaction with the Grimelius and Sevier-Munger techniques but lack of argentaffinity, positive histamine and chromogranin A immunostaining, but no serotonin immunoreactivity. Numerous histamine-immunoreactive mast cells were present in the stroma of the tumors and also in the surrounding mucosa. Our findings support the view that gastric carcinoids in patients with hypergastrinemia due to chronic atrophic gastritis are histamine-producing tumors derived from hyperplastic enterochromaffinlike cells.     

Murine experimental autoimmune gastritis models refractive to development of intrinsic factor autoantibodies, cobalamin deficiency and pernicious anemia

Researchers have developed murine lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent based models to induce an experimental autoimmune gastritis (EAG) for the study of human organ-specific autoimmune disease. These models result in a chronic inflammatory mononuclear cell infiltrate in the gastric mucosa, destruction of parietal and zymogenic cells with autoantibodies reactive to the gastric parietal cells and the gastric H+/K+ ATPase (ATP4), arguably hallmarks of a human autoimmune gastritis (AIG). In the case of AIG, it is well documented that, in addition to parietal cell antibodies being detected in up to 90% of patients, up to 70% have intrinsic factor antibodies with the later antibodies considered highly specific to patients with pernicious anemia. This is the first report specifically investigating the occurrence of intrinsic factor antibodies, cobalamin deficiency and pernicious anemia in EAG models. We conclude, in contrast to AIG, that, in the three EAG models examined, intrinsic factor is not selected as a critical autoantigen.     

Multicentric gastric carcinoids complicating pernicious anemia. Origin from the metaplastic endocrine cell population

We report three cases of multicentric carcinoid tumors of the stomach in patients with long-standing pernicious anemia and severe atrophic gastritis (type A). The tumor nodules arose in nonantral gastric mucosa showing marked intestinal metaplasia. Diffuse endocrine cell hyperplasia was present in both fundus and antrum. Antral G-cell hyperplasia was observed. A widely accepted pathogenesis of this syndrome suggests that the proliferating cell type is the argyrophilic, enterochromaffinlike cell native to the gastric body and fundus. Our findings conflict with this view, in that focal argentaffin staining was also present within tumor cells, as well as immunoreactivity for serotonin and substance P (more characteristic of small-intestinal enterochromaffin or Kulchitsky's cells and small-intestinal carcinoids). Findings in these cases at least suggest an alternative possibility: the tumors may derive from small-intestinal-type metaplastic endocrine cells within the atrophic mucosa, rather than the hypertrophic native endocrine cell population.     

Diagnosis and classification of pernicious anemia

Pernicious anemia (PA) is a complex disorder consisting of hematological, gastric and immunological alterations. Diagnosis of PA relies on histologically proven atrophic body gastritis, peripheral blood examination showing megaloblastic anemia with hypersegmented neutrophils, cobalamin deficiency and antibodies to intrinsic factor and to gastric parietal cells. Anti-parietal cell antibodies are found in 90% of patients with PA, but have low specificity and are seen in atrophic gastritis without megaloblastic anemia as well as in various autoimmune disorders. Anti-intrinsic factor antibodies are less sensitive, being found in only 60% of patients with PA, but are considered highly specific for PA. The incidence of PA increases with age and is rare in persons younger than 30 years of age. The highest prevalence is seen in Northern Europeans, especially those in the United Kingdom and Scandinavia, although PA has been reported in virtually every ethnic group. Because of the complexity of the diagnosis, PA prevalence is probably underestimated and no reliable data are available on the risk of gastric cancer as the end-stage evolution of atrophic gastritis in these patients.     

The gastric mucosal barrier: tight junction structure in gastritis and ulcer biopsies

Summary Tight junctions of the human gastric mucosa were examined using quantative freeze-fracture methods. Biopsies examined were from patients with gastric diseases including gastritis, ulcers, and pernicious anemia. No significant differences were seen in strand number or tight junction complex depth among the biopsies analyzed, however, anomalous tight junction structures were observed. Discontinuities in the tight junction complex and hyperplastic tight junctions (extensions of the apical tight junction strands radiating over the lateral plasma membrane) were seen. These alterations were not associated exclusively with either the diagnosis of gastritis or ulcers. However, a higher frequency of tight junction breaks was seen in stomach biopsies diagnosed as gastritis while those diagnosed as ulcers displayed a higher occurrence of hyperplastic tight junctions.     

Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Molecular targets in pernicious anaemia.

Autoimmune gastritis, leading to pernicious anaemia, is an organ-specific autoimmune disease characterized by chronic atrophic gastritis and circulating gastric parietal cell autoantibodies. The parietal cell autoantigens have recently been identified as the alpha and beta subunit of the gastric proton pump (H+, K+ ATPase). Here Paul Gleeson and Ban-Hock Toh discuss how the identification of these gastric parietal cell autoantigens and the development of a mouse model of autoimmune gastritis have paved the way for an understanding of the pathogenesis of the gastric lesion.     

Pernicious anaemia in the Chinese: a clinical and immunological study

Only three Chinese subjects with Addisonian pernicious anaemia have been diagnosed in a busy haematological clinic in Hong Kong during the past 15 years. The three patients are documented.

The incidence of parietal cell and intrinsic factor antibody I in the sera of 102 Chinese thyrotoxic patients was found to be comparable to that previously reported in British thyrotoxic subjects. As in the British, a correlation was observed in the Chinese thyrotoxics between the presence of gastric antibodies in the serum and atrophic gastritis. The severity of atrophic gastritis as determined by acid secretion and biopsy was comparable to that seen in British thyrotoxic subjects, but the Schilling tests in the Chinese revealed less severe degrees of mal-absorption of vitamin B₁₂.

When pernicious anaemia occurred in the Chinese, it appeared to be identical to that occurring in Western populations. Its rarity among the Chinese may be partly due to a genetic factor which may prevent the terminal stages of autoimmune atrophic gastritis from culminating in pernicious anaemia and to an environmental factor such as a high dietary intake of vitamin B₁₂ by the Chinese.

     

Expression of glycoprotein hormone alpha-subunit by endocrine cells of the oxyntic mucosa is associated with hypergastrinemia

Previous studies have shown that hyperplastic endocrine cells of the oxyntic mucosa in patients with atrophic gastritis may express immunoreactivity for the alpha-subunit of human chorionic gonadotropin (alpha-HCG, common to all glycoprotein hormones). Since this endocrine proliferation is regarded as dependent on the trophic effect of the concomitant hypergastrinemia, the relation between immunohistochemical expression of alpha-HCG by oxyntic endocrine cells and serum levels of gastrin were investigated. The study was performed on endoscopic gastric biopsies of the oxyntic mucosa from 49 patients subdivided into the following groups: A) with histologically normal mucosa and normogastrinemia (22 cases), B) with atrophic gastritis and normogastrinemia (12 cases), C) with normal mucosa and hypergastrinemia (Zollinger-Ellison syndrome, retained antrum) (7 cases) and D) with atrophic gastritis and hypergastrinemia (with or without pernicious anemia) (8 cases). The alpha-HCG immunoreactive cells were found in all hypergastrinemic patients (groups C and D), regardless of the concomitant pathological condition of the mucosa. These cells accounted for 7.8% to 44.7% of the number of Grimelius argyrophil cells in consecutive serial sections. In contrast, alpha-HCG-containing cells were exceptional or absent in most normogastrinemic patients. Their number was sizable in only two cases of group A and three cases of group B, where it ranged from 2.5% to 14.8% of the number of argyrophil cells. It was concluded that expression of alpha-HCG is another feature of oxyntic endocrine cells associated with hypergastrinemia in addition to those previously recognized such as development of hyperplasia and/or carcinoid tumors.     

Effect of gastric antigens on the in vitro migration of leucocytes from patients with atrophic gastritis and pernicious anaemia

A total of eighteen patients with pernicious anaemia (PA) ten patients with atrophic gastritis and achlorhydria but without PA, and fourteen control subjects were tested for delayed hypersensitivity to gastric antigens using the leucocyte migration test. The percentage of PAs showing inhibition of migration in the presence of a crude extract of gastric mucosa, liver mitochondria, stomach mitochondria and stomach microsomes was 50, 55, 50 and 50% respectively. The results in atrophic gastritis were 0, 20, 20 and 0% respectively and those in the fourteen control subjects were 0, 14, 7 and 14% respectively.

There was a significant difference between PA and controls with all four antigens. There was a significant difference using crude extract and stomach mitochondria and microsomes between PA and atrophic gastritis but not with liver mitochondria. There was no significant difference between atrophic gastritis and controls although the results tended to be midway between PA values and controls.

These results indicate that cell-mediated immunity is more strongly implicated in PA than it is in atrophic gastritis which has not progressed to PA.

     

ABO (H) blood group antigen expression in gastric mucosa

The A, B, O (H) blood group antigens (BGA) are glycolipids present in the plasma membranes of many different epithelial cells. Alterations in BGA expression have been described in malignant tumors and premalignant lesions. We have studied ABO (H) BGA expression in paraffin sections of gastric specimens using immunofluorescence techniques with monoclonal antibodies. 102 patients were studied. 15 with normal mucosa (NM); 16 with duodenal ulcer (DU); 23 with gastric ulcer (GU); 11 with pernicious anaemia (PA) and 37 with adenocarcinoma (AC). The expression of BGA in normal gastric mucosa is detected in surface epithelium, mucoid cell neck glands and parietal cells as well as 2/3 of antral glands. BGA expression in DU gastritis is very similar to that seen in NM. In atrophic chronic gastritis associated with GU and PA there is a significant decrease in BGA expression. In patients with PA, BGA expression is greater in antral mucosa than in fundic mucosa. Loss of BGA expression is more pronounced in atrophic chronic gastritis surrounding AC. Intestinal metaplasia shows variable BGA expression. Our results support the hypothesis that loss of BGA expression by epithelial gastric mucosal cells may be related to alterations in cellular differentiation and premalignant potential.     

The role of O-antigen polysaccharide in the activation of neutrophils by lipopolysaccharides of Salmonella species.

Autoimmune gastritis develops spontaneously in approximately 60% of BALB/c mice thymectomized neonatally. Histologically and clinically it is similar to the atrophic gastritis associated with pernicious anaemia in humans. Here we identified antigenic protein relating to the pathogenesis of autoimmune gastritis in these mice. All sera from 32 thymectomized mice with gastritis contained autoantibodies to the vesicular fraction prepared from rat gastric parietal cells. Immunoblot analysis revealed all of these to react with a 94-kD protein corresponding in molecular mass with the H+/K(+)-ATPase alpha subunit. Some sera were also reactive with 65-85-kD and/or 60-kD proteins, whose sizes correspond to the H+/K(+)-ATPase beta subunit and intrinsic factor, respectively. The finding that immuno-adsorption with these sera resulted in reduction of H+/K(+)-ATPase activity in the vesicular fraction, supported a conclusion of H+/K(+)-ATPase alpha and/or beta subunits as the antigenic proteins. After immunization of normal syngeneic mice with various doses of gastric parietal cells or their vesicular fraction, all sera from animals demonstrating atrophic gastric mucosa with lymphocyte infiltration reacted with the H+/K(+)-ATPase alpha subunit. No antibodies to other proteins were induced even in mice immunized with higher doses of antigen. We therefore conclude that H+/K(+)-ATPase alpha subunit is important as the target antigen in pathogenesis of autoimmune gastritis in neonatally thymectomized mice, probably due to a high affinity for the MHC molecule.     

Animal models of human disease: experimental autoimmune gastritis--a model for autoimmune gastritis and pernicious anemia.

Human autoimmune gastritis is an organ-specific autoimmune disease of the stomach. It is characterized by the development of disease-specific autoantibodies and a pathology that specifically targets specialized cells within the gastric environment. The autoantigens associated with this disease have been defined as the gastric H+/K+ ATPase and intrinsic factor. The development of experimental disease models has been pivotal in our contemporary understanding of autoimmunity. Here we review mouse models of autoimmune gastritis and their relevance to human autoimmune gastritis associated with pernicious anemia. We appraise some historical as well as recent studies of experimental autoimmune gastritis (EAG), highlighting key findings that have formed the basis of our current understanding of the etiology and mechanism(s) associated with autoimmune gastritis. A precise understanding of the pathogenesis of autoimmune gastritis will permit the design of innovative and rational therapeutic strategies to prevent, arrest, ameliorate or reverse the disease.     

Helicobacter colonization and histopathological profile of chronic gastritis in patients with or without dyspepsia,mucosal erosion and peptic ulcer: A morphological approach to the study of ulcerogenesis in man

Summary Helicobacter pylori colonization and the incidence, severity, activity and topography of gastritis were investigated systematically in antrum and corpus mucosal biopsies of 1177 subjects undergoing endoscopy in the absence of gastric complaints (asymptomatic, 49) or for non-ulcer dyspepsia (NUD; 631 patients, 72 of whom had gastric and/or duodenal erosions), active gastric ulcer (GU, 76 patients), active duodenal ulcer (DU, 138 patients), and healed gastric (HGU, 39 cases) or duodenal ulcer (HDU, 230 cases). In the antrum,H. pylori colonization and the incidence, severity and activity of gastritis increased progressively in the sequence asymptomatic, erosion-free NUD, erosive NUD, healed ulcer and active ulcer. The same trend was observed in the corpus as regardsH. pylori and gastritis incidence, whereas the severity and activity of gastritis were lower in active DU and erosive NUD and higher in active, proximal GU than in the remaining patients. Active DU and erosive NUD showed the highest incidence of nonatrophic gastritis and lowest type-A or AB atrophic gastritis, while active GU had lowest normal mucosa or type-A gastritis and highest type-B atrophic gastritis. In conclusion,H. pylori colonization and gastritis incidence, severity and, especially, activity of the antrum might all contribute to mucosal erosion and ulceration, whereas the same factors, at least in part and with the exception of proximal GU, seem to have a preventive role when affecting corpus mucosa.