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PubMed1978

[Increase of unsaturated transcobalamine II in autoimmune diseases; effect of immunosuppressive therapy (proceedings)].

Transcobalamin II (TC II) is a serum protein responsible for transporting vitamin B12 to the cells. A previous observation of a child with congenital TC II deficiency and agammaglobulinemia suggested that this protein plays an important role in the immune response. Accordingly, TC II levels ere determined in 32 patients with autoimmune disease (AID) (i.e. 26 with lupus erythematosus, 4 with dermatomyositis, and 2 with autoimmune hemolytic anemia) and in 40 patients with acquired immunodeficiency due to chemotherapy. It was found that elevated TC II levels corresponded to active phases of AID. Changes in TC II levels correlated better with the clinical course of AID than complement, antinuclear antibody or native DNA binding capacity. This suggests that TC II could be a valuable parameter in following up activity of AID.

Autoimmune Diseases↗
PubMed1982

Production of transcobalamin II by various murine and human cells in culture.

The ability of various murine and human cell types to secrete in vitro transcobalamin II (TCII), the vitamin B12 transport protein, was investigated. All cell types tested were found to secrete into the culture medium biologically active TCII molecules, capable of facilitating B12 uptake. The largest amounts of TCII were produced by primary cultures of murine fibroblasts and macrophages. Large quantities of TCII were also secreted by myeloma, erythroid leukemia, and macrophage-like tumor cell lines. Murine thymus cells of T lymphocyte tumors secreted only small quantities of TCII. Mouse monocytes and fibroblasts secreted considerably larger quantities of TCII than did their human counterparts. The data indicate that many cell types have the potential to produce biologically active TCII in vitro. Whether this in vitro potential also reflects in vivo biosynthetic activity is discussed.

Animals↗
PubMed1980

[Elevation of unsaturated transcobalamin II in autoimmune diseases: study of the process in lupus erythematosis and dermatomyositis].

In an earlier study concerning patients with autoimmune diseases, a more reliable correlation of clinical disease activity was found with raised concentrations of the serum protein transcobalamin II than with several tests now in common use (complement factor C3, antinuclear antibody titer and antinative DNA binding capacity). These findings were subsequently confirmed in long-term observations over 1 to 3 years: the present paper discusses 5 of 7 investigated cases (2 with SLE, 2 with dermatomyositis of changing activity, and 1 with an erroneous diagnosis of SLE) in detail.

Adolescent↗
PubMedDate not supplied

Serum transcobalamin II levels in breast carcinoma patients.

Serum levels of transcobalamin II (TCII) were determined in 139 patients with breast carcinoma. The patients were divided into two groups. Group A consisted of 74 patients with no evidence of active disease at the primary site or in complete remission. Serum levels of TCII were normal (up to 1,500 pg/ml) in 60 patients (81%) and moderatelyy elevated (up to 1,900 pg/ml) in 14 patients (19%) in this group. Group B consisted of 65 patients with active disease. Serum TCII levels were normal in 23 patients (35%) and were markedly elevated (up to 2,500 pg/ml) in 42 patients (65%). In Group B, 56 patients had widespread metastatic disease and 9 had active locoregional disease. Whether the moderately elevated TCII in the 14 patients of Group A with no evidence of disease and the normal TCII in the 23 patients of Group B with active disease is of prognostic value, will be determined by follow-up and close monitoring of the patients. Preliminary results of serial determinations of TCII indicate that changes in the TCII level generally correlate with the clinical course of the disease and the effects of therapy. These data indicate that TCII serum level may be useful as a marker for tumor activity in breast carcinoma.

Adult↗
PubMed1995

The cloning and characterization of the human transcobalamin II gene.

Transcobalamin II (TCII) is a plasma protein that binds vitamin B12 (cobalamin; Cbl) and facilitates the cellular uptake of the vitamin by receptor-mediated endocytosis. In genetic disorders that are characterized by congenital deficiency of TCII, intracellular Cbl deficiency occurs, resulting in an early onset of megaloblastic anemia that is sometimes accompanied by a neurologic disorder. To define the genetic basis for TCII deficiency, we have cloned and characterized the human gene that encodes this protein. The gene spans a minimum of 18 kbp and contains nine exons and eight introns, with a polyadenylation signal sequence located 509 bp downstream from the termination codon and a transcription initiation site beginning 158 bp upstream from the ATG translation start site. The 5' flanking DNA does not have a TATA or CCAAT regulatory element, but a 34-nucleotide stretch beginning just upstream of the CAP site contains four tandemly organized 5'-CCCC-3' tetramers. This sequence is a motif for a trans-active transcription factor (ETF) that regulates expression of the epidermal growth factor receptor gene (EGFR), which also lacks TATA and CCAAT regulatory elements. A GC-rich sequence that binds the SP1 protein is located 356 nucleotides upstream from the first of the series of CCCC tetramers. Although this GC sequence is at an unusual location with respect to the CAP site, a 507-bp fragment containing this GC box drives the chloramphenicol acetyltransferase (CAT) reporter gene after transient transfection into NIH 3T3 cells. No CAT activity was observed when a 420-bp fragment lacking this GC box but containing the ETF-binding domains was similarly transfected into this cell line. One consensus and two atypical motifs for the c-myc ligand are located downstream and upstream, respectively, of the GC box, and this could explain the elevated plasma TCII observed in some patients with multiple myeloma, as the c-myc product is overexpressed in some myeloma cells. Restriction endonuclease digestion of genomic DNA from eight normal subjects with Taq I, Hinfl, Msp I, and Bgl I identified three patterns of restriction fragment length polymorphism (RFLP). A number of the exon/intron splice junctions of human TCII, TCI, and IF genes are located in homologous regions of these proteins, providing evidence that these genes have evolved by duplication of an ancestral gene. This characterization of the TCII gene and the RFLP should facilitate the identification of the mutation(s) responsible for the genetic abnormalities of TCII expression.

Amino Acid Sequence↗
PubMed1994

Abnormally elevated serum transcobalamin II levels in patients with cerebral malaria.

Transcobalamin II (TCII) levels have been reported to be elevated in patients with many clinical conditions including proliferative reticuloendothelial system. As reactive macrophage hyperplasia frequently occurs in patients with malaria, the objective of the present study was to determine TCII in patients with Plasmodium falciparum with cerebral symptoms. The studies were performed on 14 cerebral malaria patients as well as 60 normal subjects. The mean values of serum vitamin B12 and TCII levels were significantly higher in the patient group and 6 and 7 patients had serum vitamin B12 and TCII levels higher than the normal values. There was direct relationship between serum TCII levels and BUN or creatinine levels. These findings indicated that raised serum TCII level occurred only in patients with renal insufficiency. A decreased glomerular fiLtration rate reduced the amount of vitamin B12 and TCII-B12 that filtered through the glomeruli resulting in the reduced proximal tubular cells uptake and its degradation of TCII. This reduced lysosomal enzyme activity, therefore, prolongs the intravascular TCII survival and increased secretion of TCII into the circulation. Therefore, serum TCII levels were elevated in these cerebral malaria patients.

Adult↗
PubMed1975

Vitamin B12 transport in blood. I. Congenital deficiency of transcobalamin II.

Some characteristics of vitamin B12 binding and transport in the serum of an infant with congenital hereditary transcobalamin II (TC II) deficiency were studied using the following parameters and methods: vitamin B12 level and binding capacity; electrophoretic mobility in polyacrylamide gel electrophoresis; various immunodiffusion and absorption experiments, using a specific anti-TC II antiserum and the patient's serum as antigen. The results of these studies point to a deficient synthesis of TC II. Parenteral administration of high doses of vitamin B12 was followed by rapid and complete clinical remission and the appearance of vitamin B12 binder in the alpha 2 region which is similar to "fetal binder." Thus, very high concentrations of vitamin B12, either carrier free or bound to this alpha 2 binder, were able to correct the disturbed physiology of TC II deficiency, presumably by normalization of DNA-thymine synthesis.

Humans↗
PubMed1993

[Vitamin B12 and transcobalamin in chronic myeloproliferative disorders].

Although vitamin B12 is an essential coenzyme for DNA synthesis, humans, like other mammals, are incapable of synthesizing it. The role of intrinsic factor (IF) in B12 absorption is widely known, but, in fact there exists a much more intricate and complex mechanism for the effective assimilation of this important trace element in humans. B12 binding proteins play important roles in all stages of vitamin B12 metabolism. They are involved not only in its absorption, but also in its transport in serum, uptake to cells, storage in organs, enterohepatic circulation, and elimination of its analogues. Besides IF, well-known as a vitamin B12 binding protein found in gastric juice, there are other kinds of binding proteins found in human serum which are composed to transcobalamin (TC) I, II and III. Elevation of the vitamin B12 level in chronic myelogenous leukemia was first reported in the 1950s. Since then, B12 elevation has been found to occur in other kinds of chronic myeloproliferative disorders (CMPDs) as well and to be caused by an increase of serum TC. In CMPDs, either TCI or TCIII increases, but, the degree of elevation and the type of TC involved differs for each disorder. This article describes the changes in TC of CMPD patients. With the induction of the developed radioimmunoassay for R-type B12 binding protein, many cases have been examined. In addition, detailed qualitative analysis using DEAE cellulose column chromatography has been included for conditions not previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Blast Crisis↗
PubMed1977

Radioimmunoassay for serum transcobalamin II.

A radioimmune assay for transcobalamin II (TC II) was devised from the following: (1) TC II-57Co B12 precipitated from normal serum with (NH4)2SO4 as the labeled ligand; (2) the TC II of whole serum as the standard source of TC II; (3) rabbit anti-pure TC II as the binding agent; (4) separation of the bound and free TC II-B12 by precipitation of the antibody bound with polyethylene glycol. The assay was responsive to either TC II or TC II-B12 and to TC II either pure or in crude preparations. It was not responsive to R-type binders of B12. The median TC II of 10 normal sera was 890 pg. per milliliter and of 10 sera from 10 random hospital patients was 1,010 pg. per milliliter. There was no measurable TC II in the serum of a child with congenital absence of TC II and the assay measured levels greater than 5,000 pg. per milliliter in abnormalities of TC II metabolism.

Antigen-Antibody Complex↗
PubMed1993

Functional human transcobalamin II isoproteins are secreted by insect cells using the baculovirus expression system.

Transcobalamin II (TCII) is a cobalamin (Cbl, vitamin B12)-binding protein in mammalian plasma that facilitates the cellular uptake of the vitamin. To obtain human TCII in sufficient quantity for analytical studies, the complementary DNA (cDNA) encoding TCII was inserted into the plasmid PVL 1393, and the baculovirus expressing TCII was obtained by homologous recombination in Spodoptera frugiperda (SF9) insect cells by cotransfection with the wildtype virus. Under optimized conditions, SF9 cells infected with the recombinant virus secreted 2 to 4 micrograms of TCII per milliliter of culture medium. TCII did not accumulate in the SF9 cells and seemed to be constitutively secreted as observed previously in cultured human endothelial cells. The purified recombinant TCII has the same molecular weight by SDS-PAGE as purified human TCII. The recombinant TCII cross-reacts with an antiserum to native human TCII, binds Cbl and facilitates the uptake of Cbl in eukaryotic cells by binding to the receptor for TCII-Cbl on the plasma membrane of K562 cells. Amino acid sequence analysis of the purified recombinant TCII identified two polypeptides, one identical to the amino acid sequence deduced from the cDNA and a second lacking the first and second N-terminal residues. These sequences are identical to two TCII polypeptides purified from Cohn fraction III of pooled human plasma. The two forms of recombinant TCII have the same isoelectric points as the two predominant isoprotein forms of TCII in human serum. Since the baculovirus construct contains a single cDNA that can encode only one amino acid sequence, the two isoproteins in recombinant TCII must be generated by a mechanism other than allele specific expression. A plausible mechanism for generating isoproteins of nonglycosylated peptides, such as TCII, may be by splicing of the leader peptide at alternative sites.

Amino Acid Sequence↗
PubMed1995

Serum transcobalamin II levels in patients with malaria infection.

Serum transcobalamin II (TCII) levels were determined in 56 patients with P. falciparum malaria infection. They were divided into 3 groups: severe (malarial parasite > 5% or patients with cerebral malaria or renal insufficiency), moderate (1-5% infection without complications) and mild (1% infection). Elevated serum TCII values were found only in patients with severe malaria infection. These values correlated directly with parasitemia, blood urea nitrogen and creatinine, but were not correlated with alkaline phosphatase. As 17 patients with azotemia had elevated serum TCII levels while other 3 patients with normal BUN and creatinine concentrations had serum TCII levels within the normal limits. These findings indicated that malarial patients with renal insufficiency had increased serum TCII. A possible mechanism is the reduced TCII-B12 that filtered through the glomeruli due to the reduced renal blood flow with the decreased its uptake by proximal tubular cells resulting in the decreased degradation of TCII by the tubular lysosomal enzymes. Determination of serum TCII level may be used as an indicator of renal function in malarial patients with renal insufficiency.

Biomarkers↗
PubMed1977

Circulating antibody to transcobalamin II causing retention of vitamin B12 in the blood.

A patient with recurrent pulmonary abscess, weight loss, and alcoholism was found to have extremely high serum vitamin B12 and unsaturated vitamin B12-binding capacity (UBBC) levels. While transcobalamin (TC) II was also increased, most of his UBBC was due to an abnormal binding protein which carried greater than 80% of the endogenous vitamin B12 and was not found in his saliva, granulocytes, or urine. This protein was shown to be a complex of TC II and a circulating immunoglobulin (IgGkappa and IgGlambda). Each IgG molecule appeared to bind two TC II molecules. The reacting site did not interfere with the ability of TC II to bind vitamin B12, but did interfere with its ability to transfer the vitamin to cells in vitro. The site was not identical to that reacting with anti-human TC II antibody produced in rabbits. Because of this abnormal complex, 57Co-vitamin B12 injected intravenously was cleared slowly by the patient. However, no metabolic evidence for vitamin B12 deficiency was demonstrable, although the patient initially had megaloblastic anemia apparently due to folate deficiency. The course of the vitamin B12-binding abnormalities was followed over 4 yr and appeared to fluctuate with the status of the patient's illness. The IgG-TC II complex resembled one induced in some patients with pernicious anemia by intensive treatment with long-acting vitamin B12 preparations. The mechanism of induction of the antibody formation in our patient is unknown.

Adult↗
PubMed1996

Serum transcobalamin II level in glucose-6-phosphate dehydrogenase deficient subjects with typhoid fever.

Transcobalamin II (TCII) is the vitamin B12 binding protein which is responsible for delivery of this vitamin to the tissues. High values for serum TCII have been reported in many clinical conditions. This paper describes the elevated serum TCII levels in three G-6-PD deficient patients with typhoid fever. They had severe hemolysis with hemoglobinuria associated with slight liver dysfunctions but without obvious increased serum creatinine and BUN concentrations. A remarkable increase in serum TCII level was observed during active hemolysis and decreased to the normal level within 2-3 days after hemolysis ceased. The mechanism of increased serum TCII during hemolysis is probably due to hemoglobinuria secondary to excessive hemolysis. As Hb is known to be efficiently reabsorbed by the proximal tubule cells and can competitively inhibit the tubular uptake of TCII-B12. It is possible that excess Hb interferes with TCII uptake and degradation at renal tubular cells. Therefore, the circulating TCII survival is prolonged resulting in the elevated TCII level. Furthermore, lysosomal degradation of newly synthesized TCII is a normal process that regulates the TCII secretion. Therefore, a reduced lysosome-mediated uptake of TCII-B12 by renal tubular cell may stimulate the TCII secretion as has been shown experimentally in vitro.

Adolescent↗
PubMedDate not supplied

[Transcobalamin II levels in blood plasma of children with acute leukemia].

Transcobalamin II (TcII) level was studied in plasma of 40 children with acute leukemia. TcII is a cobalamin-binding protein which mediated the cellular uptake of Cbl and interacted with surface membrane receptor of hemopoietic cells. Plasma TcII and cobalofilins were analysed by PAGE using 57Co-cyanocobalamin. In addition, the mature human placenta with high specificity and affinity to TcII receptors was applied for TcII plasma identification. As compared to control, significant difference of TcII activity in the plasma of children with ALL was noted. There were children with low and high TcII concentration vs. control (484 +/- 42 and 1166 +/- 62, p > 0.001). Therefore, it is necessary to assay individually all the biochemical parameters of Cbl-transport system of children with ALL for adequate metabolic correction.

Adolescent↗
PubMed1997

Antibodies to transcobalamin II block in vitro proliferation of leukemic cells.

The plasma protein transcobalamin II (TCII) binds and delivers cobalamin (Cbl; vitamin B12) to all cells, which internalize the TCII/Cbl complex by receptor-mediated endocytosis. Congenital deficiency of TCII results in intracellular Cbl deficiency, one effect of which is to disrupt DNA synthesis, leading to megaloblastic anemia. We report here an in vitro culture system in which cell growth is dependent on delivery of Cbl to cells by TCII. Recombinant human holo-TCII was shown to support in dose-dependent manner the growth of the human erythroleukemic cell line K562 and the murine lymphoma cell line BW5147. Free Cbl also supported cell growth; however, at 100- to 1,000-fold higher concentrations than those effective in the presence of apo-TCII. To determine if cellular depletion of Cbl could be achieved by interfering with interactions between TCII/Cbl and its cell-surface receptor, several monoclonal antibodies raised against human TCII were studied. Three antibodies, found to compete for the same binding site on TCII, proved to be effective inhibitors of TCII/Cbl-dependent cell growth. Our results suggest that monoclonal anti-TCII antibodies that block the function of this protein may prove useful in antitumor therapies.

Antibodies, Monoclonal↗
PubMed1977

The synthesis of transcobalamin II, a vitamin B12 transport protein, by stimulated mouse peritoneal macrophages.

The concentration of transcobalamin II (TCII), the vitamin B12 binding protein which delivers vitamin B12 to the tissues, was determined in stimulated and non stimulated mouse peritoneal exudate cells (PEC). Following a single intraperitoneal thioglycollate injection there was a marked increase in TCII which was shown to be produced by the adherent cells of the PEC i.e. the macrophages. It has been concluded that the PEC macrophages synthesize TCII.

Animals↗
PubMed2003

Human transcobalamin II receptor binds to Staphylococcus aureus protein A: implications as to its structure and function.

Purified human placental transcobalamin II receptor (TC II-R) dimer of molecular mass 124 kDa bound to Sepharose-linked bacterial immunoglobulin (IgG) binding proteins protein A, protein G, and protein A/G. TC II-R dimer was detected directly, by blotting human placental and rabbit and rat kidney membrane proteins with 125I-protein A, or indirectly, using antiserum to TC II-R or IgG-Fc region and 125I-protein. TC II-R antiserum, but not protein A, protein G, protein A/G, or antiserum to the IgG-Fc region, when added to culture medium of human intestinal epithelial Caco-2 cells or umbilical vein endothelial cells, inhibited ligand binding. However, protein A, protein G, protein A/G, or antiserum to the Fc region inhibited the internalization of the ligand TC II-[57Co]cyanocobalamin. Taken together, these studies strongly suggest TC II-R is an IgG-like molecule that contains an Fc-like region which is important in ligand internalization but not binding.

Animals↗
PubMed2001

Transfer of cobalamin from intrinsic factor to transcobalamin II.

The process is obscure by which cobalamin (Cbl) in the endocytosed intrinsic factor (IF)-cobalamin (Cbl) complex is released and transferred to transcobalamin II (TCII) within the enterocyte. Using recombinant IF and TCII, binding of Cbl to IF at pH 5.0 was 70% of binding at pH 7.0, whereas for TCII alone, the value was only 12%. TCII binding activity was lost rapidly at lower pH, but this was not due to protease action. TCII incubated at pH 5.0 with cathepsin L was degraded and could not subsequently bind Cbl. Thus, transfer from IF to TCII is unlikely to occur within an acid compartment. Only 13-15% of bound Cbl was released at pH 5.0 and pH 6.0 from either rat IF, human IF, or human TCII. The K(a) of human or rat IF at pH 7.5 was 2.2 nM; for TCII, the value was 0.34 nM. At pH 7.5, Cbl transfers from IF to TCII, but only to a limited extent (21%), as detected by nondenaturing electrophoresis. Transfer of Cbl from IF to TCII could not be demonstrated at pH values of 5.0 or 6.0. Thus, luminal transfer of Cbl between IF and TCII is likely to be limited, but is possible. The most likely mechanism for intracellular transfer of Cbl from IF to TCII involves initial lysosomal proteolysis of IF, with subsequent Cbl binding to TCII in a more neutral cellular compartment.

Journal Article↗