H+,K-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia.
ABSTRACT The prevalence and development of antibodies to H+,K+-ATPase were investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 93% of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l (p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A, a product of the gastric chief and mucous neck cells (median, 8.5 micrograms/l; reference range, 10-90 percentile, 64.4-195.5 micrograms/l), and elevated serum gastrin values (greater than 55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K(+)-ATPase antibody titers (r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K(+)-ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H+,K(+)-ATPase antibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease.
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ABSTRACT: Oral tolerance (OT) means systemic immunological unresponsiveness to harmless antigens present in the gastrointestinal tract. We presumed that tolerance to these antigens may also protect self-proteins that show immunological similarity to the intestinal normal flora. To investigate the existence and in vivo relevance of such a tolerogenic molecular mimicry, we focused our attention to Autoimmune Polyendocrine Syndrome type 1 (APS1) and Hemolysis, Elevated Liver Enzymes, Low Platelet count (HELLP) syndrome. APS1 is a human form of Autoimmune Regulator (AIRE) dysfunction with severely impaired central immunotolerance to a specific set of autoantigens, allowing investigation of tolerogenic mimicry by itself, without a disturbing background. HELLP syndrome is a mediocre manifestation of thrombotic microangiopathy, complicating pregnancy, with platelet-fibrin deposits in small blood vessels and transient development of autoantibodies. Impaired microcirculation in the liver is well described, while intestinal ischemia is possible but has not yet been studied. As the harmless nature of an antigen is essential for OT, ischemia-induced bacterial microinvasion represses this process. In case that oral tolerance to a bacterial homunculus is an existing way of self-protection and has an in vivo relevance when central tolerance is intact, significant intestinal ischemia--if present--is expected to promote autoimmunity in HELLP syndrome. We used an experimentally validated, highly reliable mathematical algorithm to predict the extent of immunological similarity between a certain autoantigen and intestinal bacteria. We found a strong negative correlation between the similarity of autoantigens to intestinal bacteria and the production of specific autoantibodies in APS1 (R=-0.70, P=0.002), while a positive correlation was observed in patients with predominantly the severe/moderately severe form of HELLP syndrome according to Mississippi classification (R=0.94, P=0.005). Autoantigen length inversely correlated with the production of autoantibodies in APS1 (R=-0.68, P=0.004). As a longer chain with more epitopes associates with an increased possibility of mimicry to any proteome, molecular mimicry in general--regarding at least major tissue-specific autoantigens--seems to be rather protective. Our calculations support the hypothesis that OT to an intestinal "bacterial homunculus" is an in vivo relevant mechanism of self-protection in humans, furthermore, HELLP syndrome presumably associates with significant intestinal ischemia and leak, resulting in transient autoimmunity via loss of OT.Molecular Immunology 04/2009; 46(8-9):1673-8. · 2.65 Impact Factor
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ABSTRACT: The prediction of Helicobacter pylori antibodies immunoglobulin A (IgA) and immunoglobulin G (IgG) and serum pepsinogen I (PG I) on gastric cancer occurrence was studied in a nested case-control study, based on 225 incident cancer cases and 435 matched controls from a Finnish cohort followed from 1966-1991. The odds ratio of noncardia gastric cancer between infected and noninfected persons was 3.12 (95% confidence interval (CI)=1.97-4.95) for elevated IgA and 2.88 (CI: 1.63-5.07) for elevated IgG antibodies. The odds ratio between low and high PG I was 2.24 (CI: 1.43-3.49). The strength of association was significant for IgA antibodies during the total follow-up, but for IgG antibodies this was only true for follow-up periods of 15 years or more. IgA antibodies were significantly associated with all registered histological subtypes apart from intestinal type adenocarcinoma. The highest gastric cancer risk was found among individuals with simultaneously elevated IgA and IgG antibodies and low PG I with an odds ratio of 10.9 (CI: 4.31-27.7) in comparison with those who were negative for both antibodies and had normal PG I. Elevated IgA and IgG antibodies and low PG I were not associated with cancers of the gastric cardia. The findings support the hypothesis that H. pylori infection is a cause of noncardia gastric cancer. Although elevated H. pylori IgA and IgG antibodies and low PG I independently could predict the occurrence of noncardia gastric cancer, their power to do so varied with the stage and length of the follow-up period and it increased when they were applied in combination.International Journal of Cancer 09/2006; 119(3):702-5. · 6.20 Impact Factor
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ABSTRACT: Cobalamin (vitamin B12) deficiency is more common in the elderly than in younger patients. This is because of the increased prevalence of cobalamin malabsorption in this age group, which is mainly caused by (autoimmune) atrophic body gastritis. Cobalamin supplementation is affordable and nontoxic, and it may prevent irreversible neurological damage if started early. Elderly individuals with cobalamin deficiency may present with neuropsychiatric or metabolic deficiencies, without frank macrocytic anaemia. An investigation of symptoms and/or signs includes the diagnosis of deficiency as well as any underlying cause. Deficiency states can still exist even when serum cobalamin levels are higher than the traditional lower reference limit. Cobalamin-responsive elevations of serum methylmalonic acid (MMA) and homocysteine are helpful laboratory tools for the diagnosis. The health-related reference ranges for homocysteine and MMA appear to vary with age and gender. Atrophic body gastritis is indirectly diagnosed by measuring serum levels of gastrin and pepsinogens, and it may cause dietary cobalamin malabsorption despite a normal traditional Schilling’s test. The use of gastroscopy may also be considered to diagnose dysplasia, bacterial overgrowth and intestinal villous atrophy in healthy patients with atrophic body gastritis or concomitant iron or folic acid deficiency. Elderly patients respond to cobalamin treatment as fully as younger patients, with complete haematological recovery and complete or good partial resolution of neurological deficits. Chronic dementia responds poorly but should, nevertheless, be treated if there is a metabolic deficiency (as indicated by elevated homocysteine and/or MMA levels). Patients who are at risk from cobalamin deficiency include those with a gastrointestinal predisposition (e.g. atrophic body gastritis or previous partial gastrectomy), autoimmune disorders [type 1 (insulin-dependent) diabetes mellitus and thyroid disorders], those receiving long term therapy with gastric acid inhibitors or biguanides, and those undergoing nitrous oxide anaesthesia. To date, inadequate cobalamin intake has not proven to be a major risk factor. Intervention trials of cobalamin, folic acid and pyridoxine (vitamin B6) in unselected elderly populations are currently under way.Drugs & Aging 04/1998; 12(4). · 2.65 Impact Factor