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PubMed1991

Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11.

A human gastric intrinsic factor (IF) cDNA clone was isolated using a rat cDNA clone as a probe. Comparison of the predicted amino acid sequence revealed 80% identity of human IF with rat IF. These cDNA clones were used to isolate and map two overlapping clones encoding the human IF gene. The first exon of the cloned region (exon 2) contains 30 bp of the 5' untranslated region, the signal peptide, and the first 8 amino acids of the mature protein. Exons 3-10 encode the remainder of the coding and 3' noncoding regions. Southern analysis of genomic DNA indicated the presence of a single human IF gene and also revealed the presence of strong hybridizing sequences in genomic DNA from monkey, rat, mouse, cow, and human, suggesting that the IF gene is well conserved. The IF gene was localized to human chromosome 11 by concurrent cytogenetic and cDNA probe analysis of a panel of human X mouse somatic cell hybrids. Southern analysis of genomic DNA from patients with congenital pernicious anemia (lacking intrinsic factor) revealed normal restriction fragment patterns, suggesting that a sizable gene deletion was not responsible for the deficiency.

Amino Acid Sequence↗

PubMed1982

Immunocytochemical localization of intrinsic factor--cobalamin bound to the guinea pig ileum in vivo.

The absorption of dietary cobalamin requires that a complex of intrinsic factor-cobalamin bind to specific receptors in the distal small intestine. The cellular location of these binding sites is unknown. To localize the intrinsic factor-cobalamin binding site, homogeneously purified hog intrinsic factor (7 pmol) and cobalamin (7 pmol) were instilled into ileal loops (n = 10) in anesthetized guinea pigs. Tissue controls for binding specificity were intrinsic factor-cobalamin in colon (n = 3) and jejunal (n = 3) loops, as well as intrinsic factor alone in ileal loops (n = 3). Intrinsic factor-[57Co]cobalamin was instilled in three ileal loops maintained for 90 min, and the radioactivity in the liver and kidneys was measured. Portions of each loop were washed in Krebs-Ringer buffer + Ca++, pH 7.4, or in either 1 mM Na2 ethylenediaminetetraacetic acid or in pH 4.5 acetate buffer. All tissue was processed for ultrastructural immunocytochemistry using a monospecific antisera to hog intrinsic factor as part of a well-characterized indirect immunoperoxidase method. Essentially all immunoreactive intrinsic factor-cobalamin was associated with the microvillous pits on mature ileal absorptive cells. Intrinsic factor binding was not present in colon or jejunum, or in the ileal loops instilled with intrinsic factor alone. Ethylenediaminetetraacetic acid and acid pH decreased intrinsic factor-cobalamin binding but caused severe disruption of the microvillous architecture. Absorption of [57Co]cobalamin was demonstrated, but intrinsic factor was not identified within enterocytes. The localization of specific intrinsic factor-cobalamin binding sites to the microvillous pit suggests that the intrinsic factor-cobalamin receptor may maintain a relatively fixed position within the surface membrane, and although alternative explanations are possible, our findings support the hypothesis that intrinsic factor is not internalized into the enterocyte during cobalamin absorption.

Animals↗

PubMedDate not supplied

[Transient malabsorption of Vitamin B12 bound to intrinsic factor in pernicious anemia (author's transl)].

In six patients with pernicious anemia, absorption of vitamin B12 bound to intrinsic factor was low as measured by the Schilling's test. Collection of urine was complete and the activity of intrinsic factor used was checked in other pernicious anemia patients. Nutritional deficiency, drug induced malabsorption, ileal or pancreatic diseases were excluded by clinical, radiological and biological investigations. This vitamin B12 malabsorption was selective and reversible within a few months after treatment with parenteral vitamin B12. Mechanisms of this ileal dysfunction are discussed.

Aged↗

PubMed1975

[Search for anti-intrinsic factor antibodies in the diagnosis of Biermer's anemia].

The diagnostic interest of a search for anti-intrinsic factor antibodies is emphasized from the authors research on more than 200 patients or controls. Antibodies of type I, so-called blocking antibodies, were detected in 66% of cases where the diagnosis of pernicious anemia was made. Type II, so-called precipitating antibodies, were found in 47% of patients with antibodies of type I and only in the latter. Certain etiological factors, already noted in the world literature, were found, in particular the link with the female sex and with blood group A. The specificity of these antibodies is very great and false positives are exceptional. We did not find them in any of the 104 controls. They were observed, however, in 5 of the 56 patients where the diagnosis of pernicious anemia was not definite, but it is likely that, in these 5 cases, pernicious anemia existed with some other disease. Our study also showed the limits of other methods of investigation of this disease; hypovitaminimia B12 is often corrected by treatment without proper inductions and B12 malabsorption on the Schilling test may not be corrected by the addition of intrinsic factor.

Anemia, Macrocytic↗

PubMed2006

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.

Anemia, Pernicious↗

PubMed1996

A study of intrinsic factors in patients with stress fractures of the tibia.

We aimed to study intrinsic factors in 29 consecutive patients with well-documented unilateral stress fractures of the tibia. Anthropometry, range of motion, isokinetic plantar flexor muscle performance, and gait pattern were analyzed. The uninjured leg served as the control. A reference group of 30 uninjured subjects was compared regarding gait pattern. Anterior stress fractures of the tibia (N = 10) were localized in the push-off/ landing leg in 9/10 athletes, but were similarly distributed between legs in posteromedial injuries (N = 19). Ten (30%) of the stress fracture subjects had bilateral high foot arches, similar to those found in the reference group. There were no other systematic differences in anthropometry, range of motion, gait pattern, or isokinetic plantar flexor muscle peak torque and endurance between injured and uninjured legs. No other differences were found between anterior and posteromedial stress fractures. We conclude that anterior stress fractures of the tibia occur mainly in the push-off/landing leg in athletes. Within the limitations of our protocol, no registered intrinsic factor was found to be directly associated with the occurrence of a stress fracture of the tibia.

Adolescent↗

PubMed1969

Improved method for measuring vitamin B12 in serum using intrinsic factor, 57CoB12, and coated charcoal.

An improved and simplified method is described for the measurement of vitamin B(12) in serum using intrinsic factor, (57)CoB(12), and coated charcoal. The extraction of serum in the presence of cyanide and the incorporation of B(12)-deficient serum into the intrinsic factor control has increased the accuracy of the method for both sera and crystalline B(12) solutions. There are interesting differences between the results obtained for some sera by the isotope and L. leichmannii methods and the reasons for these differences are discussed.

Biological Assay↗

PubMed1983

Separation of cobalamin analogues in human sera binding to intrinsic factor and to R-type vitamin B12 binders.

Intrinsic factor (IF) and cobalamin-R-binding protein (R-binder) linked to polyacrylamide beads were used to absorb cobalamins from solutions and serum extracts. Both binding agents were equally effective in removing [57Co]B12 from aqueous solution. IF was more effective than R-binder in removing [57Co]B12 added to a serum extract. All endogenous cobalamins detectable in serum by saturation analysis assay were removed by absorption onto R-binder. Absorption with IF removed microbiologically-active cobalamins but left behind analogues assayable with an R-binder. However, when absorption with IF was continued the concentration of R-binding cobalamins steadily declined indicating that IF bound both types of cobalamins through the binding was less avid for the microbiologically-inactive analogues than for microbiologically-active cobalamins. Finally, the R-binding analogues in serum were carried on transcobalamin I and none was detectable on transcobalamin II. The absorption studies establish the presence of two types of cobalamins one binding preferentially to IF and the other preferentially to R-binder. Only the former is detected by microbiological assay.

Absorption↗

PubMed1979

Evidence for involvement of cyclic nucleotides in intrinsic factor secretion by isolated rabbit gastric mucosa.

Secretion of intrinsic factor (IF) has previously been demonstrated in isolated rabbit fundic mucosa maintained in organ culture. We have now investigated the possibility that cyclic nucleotides may play a role in IF secretion. A phosphodiesterase inhibitor, 3-isobutyl methylxanthine (IBMX), stimulated IF secretion nearly fourfold while increasing tissue levels of both cyclic AMP (cAMP) and cyclic GMP (cGMP). Peak IF secretion in response to IBMX was not reached until after tissue cAMP levels were maximal. Dibutyryl cAMP and 8-Br-cAMP increased secretion by the same order of magnitude as did IBMX, whereas corresponding analogues of cGMP had no such effect. Histamine increased secretion of IF. In the presence of 40 microM IBMX, histamine elevated tissue levels of cAMP, but not of cGMP, and the stimulating effect of 10 microM histamine on IF secretion was potentiated. An H2 receptor antagonist, cimetidine, blocked the increases in IF secretion and tissue cAMP levels due to histamine, and the increase in IF secretion due to IBMX. These observations are consistent with a role for cAMP in the secretion of IF by isolated gastric mucosa.

1-Methyl-3-isobutylxanthine↗

PubMed1991

Molecular recognition in the binding of vitamin B12 by the cobalamin-specific Intrinsic Factor.

Equilibrium constants (given as log K/M-1) have been determined at pH 7.4 and 4 degrees C for binding by porcine Intrinsic Factor (B12-binding protein from the gut, specific for the 'cobalamin' series of Co corrinoids) of vitamin B12 or cyanocobalamin (10.5), cyanocobinamide, alpha-ribazole and alpha-ribazole-phosphate (main fragments produced by cleaving off the 'cobalamin' side-chain, all less than or equal to 3), and cyanocobinamide in the presence of greater than or equal to 10(-9) M ribazole (5.6 and independent of ribazole concentration), i.e. ribazole catalyses the binding of the cobinamide. It is proposed that the specificity of Intrinsic Factor for the cobalamins depends on the presence of the ribazole fragment in the cobalamin side-chain to promote an essential change in conformation before the corrinoid fragment can be bound.

Animals↗

PubMed1976

Lack of effect of alcohol on small intestinal binding of the vitamin B12 - intrinsic factor complex.

Absorption of 57Co-labelled vitamin B12 - intrinsic factor (IF) complex and its binding to mucosal precipitate and brush border fractions of rat small intestine was studied in rats pair-fed with a liquid diet containing ethanol 5 g/100 ml, 35% of calories, or isocalorically substituted sucrose. IF was obtained from rats fasted for 18 h. and for each experiment the amount of vitamin B12 added was the minimum required to achieve maximum binding to IF. Rats fed alcohol exhibited hepatic steatosis, proliferation of smooth endoplasmic reticulum, and disordered mitochondria after 6 weeks on the diet, and absorption of vitamin B12, fed with IF by stomach tube, was reduced signficantly. In contrast, binding of 57Co-labelled vitamin B12 -IF complex to mucosal precipitate and brush border fractions was never less than that of fractions from control rats at 4, 8 and 12 weeks on the alcohol diet. Furthermore, binding to the brush border was significantly greater in alcohol-fed rats at 12 weeks whether expressed per unit of beta-naphthylamidase (EC 3.4.1.1) activity or per milligram of protein. Total mucosal sucrase (EC 5.2.1.26) and beta-naphthylamidase were unchanged or slightly increased (beta-naphthylamidase at 12 weeks) on the alcohol-containing diet indicating that total brush border membrane was not reduced. Total brush border binding activity was the same in alcohol-fed and control rats at each time period. These results indicate that malabsorption of vitamin B12 in rats fed alcohol cannot be due to decreased binding of the vitamin B12 - IF complex by brush border membrane receptors, or secondary to a net decrease in membrane receptors.

Animals↗

PubMedDate not supplied

Gastric intrinsic factor hypersecretion stimulated by pentagastrin in cystic fibrosis.

The gastric pentagastrin-stimulated secretions of acid (peak acid output) and of unsaturated intrinsic factor in eight cystic fibrosis patients (1.4 +/- 0.5 mEq/kg/h and 0.27 +/- 0.12 nmol/kg/h, respectively) were significantly enhanced (p less than 0.05) when compared with six normal controls (0.27 +/- 0.16 mEq/kg/h and 0.10 +/- 0.02 nmol/kg/h, respectively). Despite the gastric hypersecretion of intrinsic factor, no significant physicochemical modification of this glycoprotein was observed in cystic fibrosis when using gel filtration and isoelectrofocusing. Haptocorrin (a cobalamin glycoproteic binder that does not promote the assimilation of cobalamin) also increased in gastric juice after stimulation. Since the sequestration of cobalamin to haptocorrin is pH dependent, the gastric acid hypersecretion observed in cystic fibrosis may explain that the malabsorption of crystalline cobalamin is much more frequent in cystic fibrosis than in chronic pancreatitis.

Adolescent↗

PubMed1976

Changes in the ultraviolet and circular dichroism spectra of aquo-, hydroxy-, azido-, and cyanocobalamin when bound to human intrinsic factor or human transcobalamin I.

The ultraviolet and the circular dichroic spectra of aquo-, hydroxy-, azido-, and cyanocobalamin free or bound to purified human intrinsic factor or purified human transcobalamin I were recorded. Except for azidocobalamin-transcobalamin I, the molar absorption for the gamma1-band in the ultraviolet spectra increased with a factor between 1.2 and 1.4 when the cobalamins were bound to protein. The ultraviolet spectrum of azidocobalamin-transcobalamin I changed so that the gamma2-band became the most intense. Minor changes were observed in the other ultraviolet spectra. The most prominent change in the CD-spectra of protein bound cobalamins was the increase in negative elipticity above 400 nm. This increase was most intense for cyano- and azidocobalamin-transcobalamin I. The study emphasizes that the mechanism by which human intrinsic factor and human transcobalamin I bind cobalamins differ.

Binding Sites↗

PubMed2004

An antibody specific for coagulation factor IX enhances the activity of the intrinsic factor X-activating complex.

During hemostasis the zymogen factor X (FX) is converted into its enzymatically active form factor Xa by the intrinsic FX-activating complex. This complex consists of the protease factor IXa (FIXa) that assembles, together with its cofactor, factor VIIIa, on a phospholipid surface. We have studied the functional properties of a FIXa-specific monoclonal antibody, 224AE3, which has the potential to enhance intrinsic FX activation. Binding of the antibody to FIXa improved the catalytic properties of the intrinsic FX-activating complex in two ways: (i) factor VIIIa bound to the FIXa-antibody complex with a more than 18-fold higher affinity than to FIXa, and (ii) the turnover number (kcat) of the enzyme complex increased 2- to 3-fold whereas the Km for FX remained unaffected. The ability of 224AE3 to increase the FXa-generation potential (called the "booster effect") was confirmed in factor VIII (FVIII)-depleted plasma, which was supplemented with different amounts of recombinant FVIII. In the presence of antibody 224AE3 the coagulant activity was increased 2-fold at physiological FVIII concentration and up to 15-fold at low FVIII concentrations. The booster effect that we describe demonstrates the ability of antibodies to function as an additional cofactor in an enzymatic reaction and might open up a new principle for improving the treatment of hemophilia.

Animals↗

PubMed1983

Intrinsic factor in human amniotic fluid as determined by radioimmunoassay.

The intrinsic factor (IF) concentration in 55 human amniotic fluid specimens was determined by radioimmunoassay (RIA). The antiserum was produced by immunizing rabbits with the cobalamin-IF complex isolated from human gastric juice. The median concentration of IF was 0.17 nmol/l and the extreme values less than 0.07-2.51 nmol/l. Three specimens with a clearly elevated level (0.96, 1.11 and 2.51 nmol/l) were observed. The highest value was associated with a fetal malformation, viz. obstruction of the proximal gut. There was no evident correlation between the concentration of IF in amniotic fluid and gestational age.

Adult↗

PubMed1977

Pancreatic extract and the intestinal uptake of vitamin B12. I. Effect on the intestinal epithelium and the vitamin B12-intrinsic factor complex.

Pancreatic extract (PE) reduced the uptake of rat intrinsic factor (IF)-bound 57CoB12 by perfused rat intestinal segments (p is less than 0.02) as well as by isolated rat intestinal brush borders (p is less than 0.01). The inhibition was concentration-dependent. Preincubation of the brush borders with PE recular weight of the 57CoB12-IF complex, as well as the uptake of the complex by isolated intestinal brush borders, was unchanged after prolonged preincubation with PE. PE also inhibited the uptake of glucose by perfused intestinal segments (p is less than 0.01), but the morphology and idsaccharidase activity (p is greater than 0.5) of the intestinaleptihelium was unaltered. The results indicate that the inhibition may be due to interaction between the intestinal epithelium and PE.

Animals↗

PubMed1987

Increased sensitivity of detection of the blocking (type I) anti-intrinsic factor antibody.

Increasing the ratio of test serum to the intrinsic factor (IF) antigen should increase the sensitivity of anti-IF antibody assay, a useful, specific tool for diagnosing pernicious anemia. We therefore designed an assay in which this ratio was increased 25-fold over that of our current standard assay and 1,000-fold over that of most described methods. This assay was then compared with our standard assay, with one of the original assays, and with a commercial kit. Both of our assays, especially the newer sensitive method, detected antibody in much greater dilutions of positive serum than the other assays. The sensitive assay also detected antibody in 17% of pernicious anemia sera negative by our standard technique. We calculated that anti-IF antibody can be detected with the sensitive assay in 78% of our patients with pernicious anemia, compared with 73% by our standard assay, 65% by the commercial kit, and 61% by the original method of Gottlieb and colleagues. No antibody was detected in 35 control sera with the new assay, which suggests that the increased sensitivity did not come at the expense of diminished specificity. The increased sensitivity enhances the value of the anti-IF antibody as a major screening and diagnostic tool in pernicious anemia.

Anemia, Pernicious↗

PubMed1992

Intrinsic factors associated with pressure sores in elderly people.

As a preliminary to a larger, prospective study of intrinsic factors associated with pressure sore development in a population of elderly hospital in-patients, this retrospective study of patients who had participated in an earlier, unrelated study was completed. The results of biochemical and haematological analyses from admission, together with details of nursing care, were obtained from medical and nursing notes, and analysed in relation to the condition of the pressure areas of each patient, which had been documented by a single observer throughout the period of study. The relationships between intrinsic factors such as serum protein concentration and systolic blood pressure, and the presence of, or tendency to develop pressure sores is examined and discussed in the light of a need for more specific and sensitive risk assessment tools.

Aged↗