cefoxitin and Syndrome

The idiopathic Tn-syndrome, formerly called 'permanent mixed-field polyagglutinability', is a rare hematological disorder characterized by the expression of the Tn-antigen on all blood cell lineages. The immunodominant epitope of the Tn-antigen is terminal alpha-N-acetylgalactosamine, O-glycosidically linked to protein. Normally this residue is 3'-substituted by 5-galactose thereby forming the core 1 structure known as the Thomsen-Friedenreich (TF) antigen (Galbeta1 ==> 3GalNAcalpha1 ==> Thr/Ser). The cause of the exposure of the Tn-antigen appears to be due to the silencing of the gene expression of beta1,3galactosyltransferase, since treatment of deficient Tn(+) lymphocyte T clones with 5'azacytidine or Na butyrate leads to reexpression of enzyme activity and the sialylated TF-antigen. The Tn-syndrome is acquired and permanent and affects both sexes at any age. Its origin is unknown. Pluripotent stem cells are affected since all lineages are involved but each one to a variable extent. Therefore, normal cells co-exist with Tn-transformed cells. Clinically, patients suffering from the Tn-syndrome appear healthy. Laboratory findings usually reveal moderate thrombocyto- and leukopenia and some signs of hemolytic anemia not warranting any treatment.

Topics: Anemia, Hemolytic; Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Azacitidine; Blood Cells; Erythrocyte Membrane; Galactosyltransferases; Hematologic Diseases; Humans; Lectins; Leukopenia; Molecular Structure; Syndrome; Thrombocytopenia

Topics: Antigens, Tumor-Associated, Carbohydrate; Erythrocyte Aggregation; Humans; Syndrome

Topics: Antigens; Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; Galactosyltransferases; Hematopoietic Stem Cells; Humans; Incidence; Polysaccharides; Syndrome

Tn syndrome is a rare autoimmune disease in which subpopulations of blood cells in all lineages carry an incompletely glycosylated membrane glycoprotein, known as the Tn antigen. This truncated antigen has the sugar N-acetylgalactosamine alpha-linked to either a serine or threonine amino-acid residue, whereas the correct T antigen has an additional terminal galactose; the defect may be due to a malfunction of the glycosylating enzyme T-synthase. Here we show that Tn syndrome is associated with a somatic mutation in Cosmc, a gene on the X chromosome that encodes a molecular 'chaperone' that is required for the proper folding and hence full activity of T-synthase. The production of the autoimmune Tn antigen by a glycosyltransferase enzyme rendered defective by a disabled chaperone may have implications for other Tn-related disorders such as IgA nephropathy, a condition that can result in renal failure.

Topics: Alleles; Antigens, Tumor-Associated, Carbohydrate; Autoimmune Diseases; Female; Galactosyltransferases; Genetic Diseases, X-Linked; Glycosylation; Humans; Male; Molecular Chaperones; Mutation; Syndrome

The human hematopoietic disorder named Tn syndrome has been ascribed to an acquired stem cell mutation resulting in loss of beta-1,3-galactosyltransferase activity in affected Tn+ cells of the hematopoietic lineages. Recently, we could demonstrate that this deficiency is due to a repression of a functional allele of the beta-1,3-Gal-T gene since treatment of Tn+ T-lymphocytes from a patient (R.R.) afflicted with the Tn-syndrome with 5-azacytidine or Na n-butyrate resulted in re-expression of the Thomsen-Friedenreich (TF) antigen, the product of beta-1,3-Gal-T activity [M. Thurnher, S. Rusconi, E.G. Berger. Persistent repression of functional allele can be responsible for galactosyltransferase deficiency in Tn syndrome. J. Clin. Invest. 91 (1993) 2103-2110]. To reduce these observations to a common pathogenetic mechanism responsible for the Tn-syndrome, more Tn patients need to be investigated. Here, we describe similar Tn+ T-lymphocytes cultured ex vivo from patient M.Z. whose Tn+ syndrome was newly recognized. Tn+ and TF+ T-lymphocyte cultures were characterized by flow cytometry and measurement of beta-1,3-Gal-T and shown to be deficient in Tn+ cells. Furthermore, Tn+ cells were treated with 5-azacytidine and Na n-butyrate as described before. Reoccurrence of beta-1,3-Gal-T activity dependent epitopes on the cell surface of Tn+ cells was shown by flow cytometry. These support the notion of beta-1,3-Gal-T gene repression as a common pathogenetic mechanism underlying the Tn-syndrome.

Topics: Antigens, Tumor-Associated, Carbohydrate; Biomarkers; Galactosyltransferases; Gene Expression Regulation, Enzymologic; Hematologic Diseases; Humans; Syndrome

Previously, beta 1,3-galactosyltransferase-deficient (Tn+) and normal (TF+) T-lymphocyte clones have been established from a patient suffering from Tn-syndrome [Thurnher et al. (1992) Eur J Immunol 22: 1835-42]. Tn+ T lymphocytes express only Tn antigen GalNAc alpha 1-O-R) while other O-glycan structures such as sialosyl-Tn (Neu5Ac alpha 2,6GalNAc alpha 1-O-R) or TF (Gal beta 1-3GalNAc alpha 1-O-R) antigens are absent from these cells as shown by flow cytometry using specific mABs for TF and sialosyl-Tn antigen, respectively. Normal T lymphocytes express the TF antigen and derivatives thereof. The surface glycans of Tn+ and TF+ cells were then analysed by flow cytometry using the following sialic acid-binding lectins: Amaranthus caudatus (ACA), Maackia amurensis (MAA), Limax flavus (LFA), Sambucus nigra (SNA) and Triticum vulgare (WGA). Equal and weak binding of MAA and SNA to both TF+ and Tn+ cells was found. WGA, LFA and ACA bound more strongly to TF+ cells than to Tn+ cells. Binding of ACA to TF+ cells was enhanced after sialidase treatment. To investigate the possible biological consequences of hyposialylation, binding of three sialic acid-dependent adhesion molecules to Tn+ and TF+ cells was estimated using radiolabelled Fc-chimeras of sialoadhesin (Sn), myelin-associated glycoprotein (MAG) and CD22. Equal and strong binding of human CD22 to both TF+ and Tn+ cells was found. Whereas binding of Sn and MAG to TF+ cells was strong (100%), binding to Tn+ cells amounted only to 33% (Sn) and 19% (MAG). These results indicate that the in vivo interactions of T lymphocytes in the Tn syndrome with CD22 are not likely to be affected, whereas adhesion mediated by Sn or MAG could be strongly reduced.

Topics: Animals; Antigens, Tumor-Associated, Carbohydrate; Carbohydrate Sequence; Clone Cells; Hematologic Diseases; Humans; Lectins; Molecular Sequence Data; N-Acetylneuraminic Acid; Plant Lectins; Plants; Protein Binding; Syndrome; T-Lymphocytes

Topics: Adolescent; Arthritis, Infectious; Bacteremia; Cefoxitin; Clindamycin; Fusobacterium Infections; Fusobacterium necrophorum; Humans; Jugular Veins; Male; Metronidazole; Peritonsillar Abscess; Pharyngitis; Syndrome; Thrombophlebitis

The Tn syndrome is an acquired form of persistent mixed-field polyagglutination displaying two distinct populations of Tn positive (Tn) and Tn negative (tn) red blood cells (RBCs). We investigated the electrophoretic behavior of RBCs showing polyagglutination from a patient with Tn syndrome by the doppler electrophoretic light scattering (D.E.L.S.) analysis. The mean of zeta potential of normal RBCs from ten individuals was -13.07 +/- 0.61 mV (mean +/- S.D.). The content of membrane-associated sialic acid equated with the zeta potential of RBCs. Among the proteases ficin was most effective on the zeta potential of RBCs. The zeta potential of the patient Tn RBCs and tn RBCs were -4.73 mV and -13.32 mV, respectively. Tn RBCs reduced 64.5% of zeta potential compared with tn RBCs and formed 48.8%. These results may provide some useful information for classification of Tn syndrome.

Topics: Antigens, Tumor-Associated, Carbohydrate; Doppler Effect; Electrophoresis; Enzymes; Erythrocyte Membrane; Erythrocytes; Hemagglutination; Hematologic Diseases; Humans; Light; Male; Middle Aged; N-Acetylneuraminic Acid; Scattering, Radiation; Sialic Acids; Surface Properties; Syndrome

A human hematopoietic disorder designated as Tn syndrome or permanent mixed-field polyagglutinability has been ascribed to a stem cell mutation leading to a specific deficiency of UDP-Gal:GalNAc alpha 1-O-Ser/Thr beta 1-3 galactosyltransferase (beta 3 Gal-T) activity in affected cells. To test for the possibility that an allele of the beta 3Gal-T gene might be repressed instead of mutated, we have investigated whether 5-azacytidine or sodium n-butyrate, both inducers of gene expression, would reactivate expression of beta 3Gal-T in cloned enzyme-deficient T cells derived from a patient affected by the Tn syndrome. Flow cytometry revealed that a single treatment induced de novo expression of the Thomsen-Friedenreich antigen (Gal beta 1-3GalNAc-R), the product of beta 3Gal-T activity. In addition, a sialylated epitope on CD43 (leukosialin), which is present on normal but not on beta 3Gal-T-deficient T cells, was also reexpressed. Although no beta 3Gal-T activity was detectable in untreated Tn syndrome T cells, after exposure to 5-azaC,beta 3Gal-T activity reached nearly normal values. Both agents failed to reactivate beta 3Gal-T in Jurkat T leukemic cells, which also lack beta 3Gal-T activity. These data demonstrate that Tn syndrome T cells contain an intact beta 3Gal-T gene copy and that the enzyme deficiency in this patient is due to a persistent and complete but reversible repression of a functional allele. In contrast, the cause of beta 3Gal-T deficiency appears to be different in Jurkat T cells.

Topics: Alleles; Antigens, Tumor-Associated, Carbohydrate; Azacitidine; Butyrates; Butyric Acid; Carbohydrate Sequence; Clone Cells; Enzyme Repression; Galactosyltransferases; Hematologic Diseases; Humans; Kinetics; Molecular Sequence Data; Syndrome; T-Lymphocytes; Tumor Cells, Cultured

A Japanese male patient with myelodysplastic syndrome (MDS) was shown to have associated Tn syndrome; the first report of Tn syndrome with MDS. The Tn expression was demonstrated on erythrocytes, granulocytes, monocytes, platelets, and lymphocytes by flow cytometric analysis using a lectin and an antibody. Electrophoresis of erythrocyte membrane proteins revealed slower mobility of glycophorin B from the patient than that from normal individuals, suggesting a glycophorin B molecular abnormality.

Topics: Antigens, Tumor-Associated, Carbohydrate; Erythrocytes; Glycophorins; Hematologic Diseases; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Syndrome

In order to examine expression of the Tn antigen on erythroid cells from a patient with Tn syndrome, we applied a selective two phase liquid culture system for human erythroid progenitors in peripheral blood. The cells were analyzed with flow cytometry employing an anti-Tn antibody and a lectin of Vicia villosa which recognizes only the Tn determinant. In the second phase, the Tn antigen was expressed on the cultured cells from the patient on day 3 and Tn-positive cells reached 62.7% on day 9. On the other hand, Tn-positive cells were not detected in the volunteer's cultured cells. When the patient's cells were co-cultured with the cells from a healthy volunteer, the percentage of Tn-positive cells was much lower than the expected value, suggesting that the normal cells suppressed the expression of Tn antigen on the patient's cells.

Topics: Acetylgalactosamine; Anemia, Refractory, with Excess of Blasts; Antigens, Surface; Antigens, Tumor-Associated, Carbohydrate; Cell Differentiation; Erythrocyte Aggregation; Erythrocytes, Abnormal; Erythroid Precursor Cells; Flow Cytometry; Galactosyltransferases; Hemagglutination Tests; Hematologic Diseases; Humans; Male; Membrane Glycoproteins; Middle Aged; Syndrome

Flow cytometric analysis employing monoclonal antibodies to the Tn antigen and glycophorin A was used to characterize the erythrocyte populations present in blood samples from individuals with Tn syndrome. Four monoclonal antibodies specific for the Tn antigen, Gal-NAc monosaccharide, on human erythrocytes were obtained from a fusion of splenocytes from a Biozzi mouse immunized with red cells from a Tn individual. These monoclonal antibodies specifically recognize GalNAc monosaccharide sites located on the erythrocyte cell surface sialoglycoproteins, glycophorin A and glycophorin B, and do not bind to fixed normal red cells presenting the Neu-NAc alpha 2-3Gal beta 1-3(NeuNAc alpha 2-6)GalNAc alpha 1-O-Ser(Thr) tetrasaccharide or to fixed neuraminidase-digested cells presenting the Gal-GalNAc disaccharide. The percentages of Tn-positive red cells in samples from six unrelated Tn donors ranged from 28 to 99%. Binding of the glycophorin A-specific monoclonal antibodies showed that the erythrocytes composing the Tn-negative fraction presented normal amounts of the M and N epitopes on glycophorin A. The presumed somatic mutational origin of Tn-positive cells was tested in blood samples from five normal donors; three possible Tn cells were observed after analysis of a total of 1.1 x 10(7) erythrocytes, suggesting that the frequency of such cells in normal individuals is less than 1 x 10(-6).

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Biomarkers; Blood Group Antigens; Cell Separation; Enzyme-Linked Immunosorbent Assay; Epitopes; Erythrocytes; Flow Cytometry; Glycophorins; Hemagglutination Tests; Humans; MNSs Blood-Group System; Mutation; Sialoglycoproteins; Syndrome

Topics: Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Binding Sites; Blood Platelet Disorders; Carbohydrates; Humans; Lectins; Platelet Membrane Glycoproteins; Syndrome

Topics: Adolescent; Cefoxitin; Female; Humans; Psychoses, Substance-Induced; Syndrome

The Tn syndrome is an acquired clonal disorder characterized by the exposure of a normally hidden determinant, the Tn antigen, on the surface of human erythrocytes, platelets, granulocytes, and lymphocytes. Two distinct populations, Tn positive (Tn+) and Tn negative (Tn-), of mature hemopoietic cells are present in Tn patients. To determine whether the Tn antigen is already expressed on erythroid, myeloid, and pluripotent progenitors, light-density mononuclear blood cells from two patients with this syndrome were separated by fluorescent-activated cell sorting and by affinity chromatography into Tn+ and Tn- fractions, using their binding properties to Helix pomatia agglutinin (HPA). Burst-forming-unit erythroid (BFU-E), colony-forming-unit granulocyte/macrophage (CFU-GM), cells were assayed in plasma clot cultures. After 12-14 d of culture, colonies were studied by a double fluorescent labeling procedure. First, a fluorescein-conjugated HPA permitted evaluation of the presence or absence of the Tn antigen at the surface of the cells composing each colony, and second, the binding of a murine monoclonal antibody against either glycophorin A (LICR-LON-R10) or against a myeloid antigen (80H5), revealed by an indirect fluorescent procedure, was used to establish the erythroid or myeloid origin of each cell. The Tn+ fraction obtained by cell sorting gave rise to nearly 100% Tn+ colonies composed exclusively of cells bearing this antigen. The reverse was observed for the Tn- cell fraction. These results demonstrate that in the Tn syndrome, BFU-E, CFU-GM, and CFU-GEMM of the Tn+ clone express the Tn antigen at this early stage of differentiation.

Topics: Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Clone Cells; Hematologic Diseases; Hematopoietic Stem Cells; Humans; Syndrome

Topics: Adolescent; Adult; Cefoxitin; Colposcopy; Female; Humans; Pregnancy; Shock, Septic; Staphylococcus aureus; Syndrome; Ulcer; Vaginal Diseases