Intrinsic Factor Autoantibodies Research Articles

Intrinsic factor autoantibodies by luminescent immuno-precipitation system in patients with corpus atrophic gastritis

BackgroundCorpus atrophic gastritis (CAG) may lead to intrinsic factor (IF) deficiency and vitamin B12 malabsorption. Intrinsic factor autoantibodies (IFA) are considered markers of pernicious anemia, but their clinical utility in CAG has not been evaluated. This study aimed to assess IFA in CAG patients and controls using a luciferase immunoprecipitation system (LIPS). MethodsRecombinant nanoluciferase-tagged IF secreted from transfected Expi293F cells was used as antigen in an IFA-LIPS assay. IFA IgG were measured in sera from subjects undergoing gastroscopy and biopsy (updated Sydney system) mainly for anemia (57%) or dyspepsia (34%). This cohort comprised 105 patients with histologically-proven-CAG (cases: median age 64 years, 68% females) and 110 subjects with suspected CAG that were histologically negative (controls: median age 67 years, 54% females). Cut-off values were selected by Q-Q-plot analysis (negative: <2.5 arbitrary units). ResultsIFA levels were higher in cases than in controls (Mann-Whitney:p < 10−5). The ROC-AUC was 0.67 (95%CI 0.60–0.73, p < 0.0001). The IFA LIPS sensitivity and specificity for CAG were 32% (95% CI 24–42) and 95% (95% CI 90–99). This diagnostic performance remained similar after stratification for the presence/absence of anemia, dyspepsia or vitamin B12 deficiency. IFA levels were higher in females compared with males (p = 0.0127). In females aged <65 years, IFA-positives were more prevalent than in males (43.5% vs 6.6%, p = 0.011). ConclusionsThe IFA-LIPS assay discriminated between CAG patients and controls showing a good specificity (95%) at the cost of sensitivity (32%). IFA-positivity occurred independently from anemia and vitamin B12 deficiency, but was more frequent in younger females. IFA testing should be considered in patients at high clinical suspicion of CAG.

Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity.

The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed. To investigate CgA utility as a marker of endocrine autoimmunity. CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology. Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080). CgA qualifies as a novel biomarker for T1D, AP, and AG.

Intrinsic factor Recognition Promotes Th17/Th1 Autoimmune Gastric Inflammation in Patients with Pernicious Anemia

Abstract The intrinsic factor (IF) is the major humoral autoantigen in pernicious anemia (PA)/autoimmune gastritis. Although many studies have examined the autoantibody response to intrinsic factor and H+,K+-ATPase, no information is available on possible pathogenic mechanisms mediated by IF-specific gastric T cells. The aim of this study was to investigate IF-specific T cells in the gastric mucosa of PA patients and define their functional properties. In vivo-activated T cells from the infiltrates of the gastric mucosa of PA patients were isolated and cloned. We investigated the ability of the gastric T-cell clones to proliferate and produce cytokines in response to IF, as well as their helper function for antibody production and their cytolytic potential. For the first time we provide evidence that gastric mucosa of PA patients harbour a high proportion (20%) of autoreactive activated CD4+ T-cell clones that specifically recognize IF. Most of these clones (94%) showed a Th17 or Th1 profile. Virtually all IF-specific clones produced TNFα, IL-21 and provided substantial help for B-cell immunoglobulin production. Most mucosa-derived IF-specific T-cell clones expressed perforin-mediated cytotoxicity and induced Fas-Fas ligand-mediated apoptosis in target cells. Altogether, our results suggest that chronic autoantigen-induced T cell– dependent B-cell activation is responsible for the local synthesis of IF autoantibodies found in the sera and indicate that activation of IF-specific Th17 and Th1 T cells in the gastric mucosa represent a key effector mechanism in PA suggesting that the Th17/Th1 pathway may represent a novel target for the prevention and treatment of the disease.

Atrophic Body Gastritis: Clinical Presentation, Diagnosis, and Outcome

Atrophic body gastritis is a chronic disorder characterised by atrophy of the oxyntic glands leading to reduced gastric acid and intrinsic factor secretion. Serological studies reported yearly prevalence and incidence rates between 3–9% and 0–11%, respectively. In atrophic body gastritis, the presence of parietal cells and/or intrinsic factor autoantibodies, and autoimmune diseases, such as autoimmune thyroid disease or Type 1 diabetes mellitus, are often observed. These cases are often diagnosed as autoimmune gastritis. This association has been included as part of the autoimmune polyendocrine syndrome. A frequent clinical presentation of atrophic body gastritis is pernicious anaemia, considered an autoimmune condition, arising from vitamin B12 malabsorption as a consequence of intrinsic factor deficiency. Another presentation may be an otherwise unexplained iron deficiency anaemia, as a result of iron malabsorption and consequence of reduced gastric acid secretion. To date, no universally accepted criteria are available to define autoimmune gastritis and to distinguish this clinical entity from chronic, Helicobacter pylori-driven, multifocal atrophic gastritis. In contrast with the classical perception of a silent condition, patients with atrophic body gastritis may complain of a spectrum of gastrointestinal symptoms, ranging from dyspepsia as early satiety, postprandial fullness, and epigastric pain, to gastro-oesophageal reflux symptoms such as regurgitation and heartburn. The timely diagnosis of atrophic body gastritis is important, as this condition puts patients at an increased risk of gastric cancer and other Type 1 carcinoids that may lead to micronutrient deficiencies crucial for erythropoiesis. The present review provides an update on epidemiological and clinical aspects as well as diagnosis and outcome of the disease.

Autoimmune gastritis presenting as iron deficiency anemia in childhood.

To characterize clinical, laboratorial, and histological profile of pediatric autoimmune gastritis in the setting of unexplained iron deficiency anemia investigation. A descriptive, observational study including pediatric patients with a diagnosis of autoimmune gastritis (positive parietal cell antibody and gastric corpus atrophy) established in a 6 year period (2006-2011) in the setting of refractory iron deficiency anemia (refractoriness to oral iron therapy for at least 6 mo and requirement for intravenous iron therapy) investigation, after exclusion of other potentially contributing causes of anemia. Helicobacter pylori (H. pylori) infection and anti-secretory therapy were also excluded. Data were retrospectively collected from clinical files, including: demographic data (age, gender, and ethnic background), past medical history, gastrointestinal symptoms, familial history, laboratorial evaluation (Hb, serum ferritin, serum gastrin, pepsinogen I/ pepsinogen II, B12 vitamin, intrinsic factor autoantibodies, thyroid autoantibodies, and anti-transglutaminase antibodies), and endoscopic and histological findings (HE, Periodic Acid-Schiff/Alcian blue, gastrin, chromogranin A and immunochemistry analysis for CD3, CD20 and CD68). Descriptive statistical analysis was performed (mean, median, and standard deviation). We report a case-series concerning 3 girls and 2 boys with a mean age of 13.6 ± 2.8 years (3 Caucasian and 2 African). One girl had type I diabetes. Familial history was positive in 4/5 cases, respectively for autoimmune thyroiditis (2/5), sarcoidosis (1/5) and multiple myeloma (1/5). Laboratorial evaluation on admission included: Hb: 9.5 ± 0.7 g/dL; serum ferritin: 4.0 ± 0.9 ng/mL; serum gastrin: 393 ± 286 pg/mL; low pepsinogen I/ pepsinogen II ratio in 1/5 patients; normal vitamin B12 levels (analyzed in 3 patients). Endoscopy findings included: duodenal nodularity (2/5) and gastric fold softening (2/5), and histological evaluation showed corpus atrophic gastritis with lymphocytic infiltration (5/5), patchy oxyntic gland mononuclear cell infiltration (5/5), intestinal and/or pseudo-pyloric metaplasia in corpus mucosa (4/5), and enterochromaffin cell hyperplasia (4/5). Immunochemistry for gastrin on corpus biopsies was negative in all cases. Duodenal histology was normal. All biopsies were negative for H. pylori (Giemsa staining and cultural examination). We highlight autoimmune gastritis as a diagnosis to be considered when investigating refractory iron deficiency anemia in children, particularly in the setting of a personal/familial history of autoimmune disease, as well as the diagnostic contribution of a careful immunohistological evaluation.

Levels of holo-transcobalamin are more closely associated with pernicious anaemia than total B12 levels

<h3>Aims</h3> Vitamin B12 deficiency is usually due to dietary factors, however clinicians always consider the possibility of autoimmune pernicious anaemia. The Schillings test is no longer routinely available and therefore diagnosis often includes the specific intrinsic factor auto-antibodies (IFAb) +/– parietal cell auto-antibodies (PCAb). Holo-transcobalamin (HoloTC), also known as active B12, has proved to be a more reliable indicator of B12 deficiency than measuring total B12 (TB12). We therefore reviewed our experience with this test to see if HoloTC was more closely associated with pernicious anaemia testing. <h3>Methods</h3> We reviewed 1359 patients where HoloTC +/– TB12 was measured as well as one or more of IFAb and PCAb. We used each patient's first B12 result(s) for the analysis. HoloTC was measured by Abbott AxSym and total B12 was measured by Abbott Architect. PCAb antibodies are detected by immunofluor-escence whereas IFAb are measured by Alegria automated ELISA. <h3>Results</h3> When HoloTC was very low (<10pmol/L), 21% of patients had positive IFAb and 42% had positive PCAb. When HoloTC was mildly low (10–22pmol/L), 8% had positive IFAb and 18% had positive PCAb. For very low TB12 (<100pmol/L), 8% had positive IFAb and 24% had positive PCAb. When TB12 was mildly low (100–149pmol/L), 4% had positive IFAb and 11% had positive PCAb. <h3>Conclusions</h3> PCAb were more likely to be positive at any B12 level consistent with its known poor specificity. The more specific IFAb positivity is more likely to be associated with low HoloTC levels than low TB12 levels.

Diagnosis and Management of Pernicious Anemia

Pernicious anemia is a macrocytic anemia due to cobalamin deficiency, which is the result of intrinsic factor deficiency. Pernicious anemia is associated with atrophic body gastritis, whose diagnostic criteria are based on the histologic evidence of gastric body atrophy associated with hypochlorhydria. Serological markers suggesting the presence of oxyntic mucosa damage are increased levels of fasting gastrin and decreased levels of Pepsinogen I. Without the now obsolete Schilling's test, intrinsic factor deficiency may not be proven, and gastric intrinsic factor output after pentagastric stimulation has been proposed. Intrinsic factor autoantibodies are useful surrogate markers of pernicious anemia. The management of patients with pernicious anemia should focus on the life-long replacement treatment with cobalamin and the monitoring to early diagnose an eventual onset of iron deficiency. Moreover, these patients should be advised about possible gastrointestinal long-term consequences, such as gastric cancer and carcinoids.

Reassessment of Intrinsic Factor and Parietal Cell Autoantibodies in Atrophic Gastritis With Respect to Cobalamin Deficiency

Atrophic body gastritis (ABG) is an autoimmune condition eventually manifesting itself as pernicious anemia (PA). Parietal cell autoantibodies (PCAs) and intrinsic factor autoantibodies (IFAs) are considered characteristics of these conditions. Recent studies on IFA and PCA frequency with respect to cobalamin deficiency in biopsy-proven ABG patients are lacking. We addressed this issue using new enzyme-linked immunosorbent assay (ELISA)-based assays. Sera from 165 patients with histologically diagnosed ABG and 113 controls were tested for IFA and PCA using ELISA. A total of 81 ABG patients had cobalamin deficiency and macrocytic anemia (Group 1-PA), 36 had cobalamin deficiency without macrocytic anemia (Group 2), and 48 had normal cobalamin levels (Group 3). IFAs were detected in 44/165 ABG patients (27% sensitivity) and in 0/113 controls (100% specificity). PCAs were detected in 134 ABG patients (81% sensitivity) and in 11 controls (90% specificity). In Group 1, IFAs showed 37% sensitivity and 100% specificity, whereas PCAs showed 81% sensitivity and 90% specificity. Combining IFA and PCA testing increased the sensitivity to 61% in all ABG patients and to 73% in Group 1, while maintaining 100% specificity. IFAs are 100% specific for biopsy-proven ABG and occurred in 27% of patients. PCAs occurred in 81% of ABG patients and in 10% of controls. Combining IFA and PCA testing significantly increases their diagnostic performance for ABG and PA, yielding a 73% sensitivity for PA. The non-invasive combined PCA and IFA assessment may be useful in selecting patients at risk for autoimmune gastritis to be confirmed by gastroscopic-histologic examination.

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.

Organ‐Specific Autoantibodies in Children with Helicobacter pylori Infection

We compared the prevalence of organ-specific autoantibodies in a group of Helicobacter pylori infected children and a group of uninfected children and investigated the relationship between the presence of relevant autoantibodies and the status of the target organs. One hundred and twenty-four children with dyspepsia (54 boys, 70 girls; mean age 10.5 years; range 4-19) underwent gastroscopy: 56 had H. pylori infection (31 girls, 25 boys), while 68 (37 girls and 31 boys), were H. pylori-negative. All sera were tested for the presence of: parietal cell autoantibodies (PCA), intrinsic factor autoantibodies (IFA), microsomial autoantibodies, thyroglobulin autoantibodies, islet cell autoantibodies, glutamic acid decarboxylase autoantibodies, adrenal cortex autoantibodies, steroid-producing cell autoantibodies; gastrin, pepsinogen A, pepsinogen C and anti-H. pylori antibodies. The histological features and the ureA and cagA genes were also considered. The frequency of organ-specific autoantibodies was higher in patients with H. pylori infection than in uninfected patients (chi2-test p < .0001). Specifically gastric autoantibodies were significantly higher: seven of the 56 H. pylori-positive children were PCA-positive and one was IFA-positive (chi2-test p = .0004). The presence of autoantibodies was not associated with any clinical or biohumoral signs of disease. Our study detected a relationship between H. pylori infection in childhood and the presence of organ-specific autoantibodies unassociated with any clinical or biohumoral signs of disease. Helicobacter pylori infection in childhood could trigger the onset of clinical autoimmune gastritis, and/or other clinical autoimmune diseases.

Occurrence of autoantibodies against intrinsic factor, H,K-ATPase, and pepsinogen in atrophic gastritis and rheumatoid arthritis.

The occurrence of autoantibodies against intrinsic factor, H,K-ATPase, and pepsinogen was analysed by means of enzyme-linked immunosorbent assay in three groups of sera. Group 1 comprised sera from 14 rheumatoid arthritis patients with normal acid secretion; group 2, sera from 18 rheumatoid arthritis patients with reduced acid secretion; and group 3, sera from 11 patients with pernicious anaemia or achylia. Groups 1 and 2 were rheumatoid factor-positive, and group 3 was negative. Intrinsic factor autoantibodies were low in groups 1 and 2. In group 3, 9 of the 11 sera (82%) scored positive. The highest titres of H,K-ATPase and pepsinogen autoantibodies were found in groups 2 and 3. Only one serum in group 1 scored positive against H,K-ATPase, and two against pepsinogen, whereas corresponding values were 11 (61%) and 7 (39%) in group 2, and 10 (91%) and 6 (55%) in group 3. Autoantibodies against H,K-ATPase from a pool of patient sera recognized both the alpha- and beta-subunits of the enzyme. The present results support the hypothesis of an autoimmune disease overlap between non-organ-specific rheumatoid arthritis and organ-specific pernicious anaemia.

A case of Addison-Biermer type pernicious anemia associated with intrinsic factor autoantibodies in serum and gastric juice.

A case of Addison-Biermer type pernicious anemia associated with intrinsic factor autoantibodies in serum and gastric juice.

Polycythemia Rubra Vera With Pernicious Anemia Some Observations on Vitamin B12 Metabolism

Abstract A patient with polycythemia rubra vera developed symptoms and signs of pernicious anemia three years after institution of therapy for the polycythemia. This is the first satisfactorily documented report of this sequence. Strict criteria utilized make both diagnoses unequivocal. Autoantibody studies, the first performed in such a patient, show the presence of parietal cell and intrinsic factor autoantibodies but no antibodies to other tissues. Vitamin B12 requirements have been excessive despite high or high normal serum levels and extreme marrow sensitivity to withdrawal of the Vitamin is evident in the presence of these high serum levels. Studies on Vitamin B12 binding proteins showed an elevation in α binding globulin with reversal of the α to β ratio. It is suggested that this protein is physiologically abnormal. The literature is briefly reviewed regarding the pathogenesis of the two disorders with the conclusion that their appearance in the one patient represents purely a chance phenomenon.

Studies of Human Intrinsic Factor Auto-Antibodies.

Excerpt Previous studies from this and other laboratories have shown evidence for the existence of two distinct types of autoantibody to human intrinsic factor in the sera of some patients with per...

Studies of Human Intrinsic Factor Auto-Antibodies

Summary A study of the sera of 19 patients with pernicious anemia by radioimmunodiffusion, by a charcoal adsorption assay and by gel filtration with Sephadex G100, showed conclusive evidence for the occurrence of two types of antibody to human intrinsic factor in the serum of some of these patients. One type of antibody, the “blocking” antibody, detected by the charcoal adsorption assay, reacted with intrinsic factor to prevent subsequent formation of the B12-intrinsic factor complex. Blocking antibody was unable to react with preformed intrinsic factor-B12 complex. The second type of antibody, “binding” antibody, was shown to react either with the intrinsic factor itself or with the intrinsic factor-B12 complex. Although this antibody reacted with intrinsic factor alone, it did not prevent the subsequent combination of intrinsic factor with vitamin B12 which occurred without displacement of the antibody by the B12. Of the 19 sera studied, eight showed the presence of both antibodies, in two the blocking antibody only was detected, and in one only the binding antibody. The antibodies varied in amount independently of one another. From the small number of patients studied, it did not appear that one occurred much more frequently than the other, and there was no obvious correlation between the presence of antibodies and the age of the patient or the duration of the disease. Instrinsic factor which had formed a complex with the binding antibody could still react with the blocking antibody. This reaction occurred without displacement of the binding antibody, indicating that the intrinsic factor molecule has two distinct antigenically reactive sites.