title: Differences in the regulation of specific glycosylation in the pathogenesis of paroxysmal nocturnal hemoglobinuria and the Tn-syndrome.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder that resembles in several aspects the Tn-syndrome, in which bone marrow-derived cells are deficient in mucin-type beta 1,3 galactosyltransferase (beta 1,3Gal-T) due to the persistent repression of an intact allele. In the present study, we have investigated phytohemagglutinin (PHA)-activated T cells from the peripheral blood of an individual with the well-established clinical diagnosis of PNH. Only 10% of T cells were deficient in surface expression of the glycosylphosphatidylinositol (GPI)-linked CD48 antigen; in contrast, 95% of the patient's polymorphonuclear leukocytes harbored the defect. The cell-surface density of CD48 on unaffected T cells from this patient was two- to three-fold higher when compared to PHA-activated normal donor T cells. CD48-negative T cells were cloned and shown to belong to the CD4+ or the CD8+ antigenic subset. To test for the possibility that in PNH, as in Tn syndrome, gene repression may be responsible for the deficiency, CD48- T cell clones were treated with 5-azacytidine (5-azaC) and sodium n-butyrate (NaB). While such treatment reproducibly led to reexpression of a sialylated CD43 epitope on affected Tn-syndrome T cell clones, these drugs failed to induce reexpression of CD48 on affected PNH T cell clones. Our data suggest that despite many similarities, different pathogenetic mechanisms are responsible for PNH and Tn-syndrome. These CD48- T cell clones are the first to be described and may be useful to define the PNH lesion at a biochemical and genetic level.
authors.affiliation: Institute of Physiology, University of Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Thurnher
authors.forename: J
authors.initials: J
authors.lastname: Fehr
authors.forename: E G
authors.initials: EG
authors.lastname: Berger
mesh_terms: D000328:Adult; D000483:Alleles; D015703:Antigens, CD / Q000032:analysis; D001374:Azacitidine / Q000494:pharmacology; D001853:Bone Marrow / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D000071178:CD48 Antigen; D016827:CD8 Antigens / Q000032:analysis; D002478:Cells, Cultured; D005434:Flow Cytometry; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006031:Glycosylation; D006402:Hematologic Diseases / Q000209:etiology* / Q000503:physiopathology; D006457:Hemoglobinuria, Paroxysmal / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051917:Leukosialin; D008297:Male; D012795:Sialoglycoproteins / Q000032:analysis; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D015703:Antigens, CD; D002087:Butyrates; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D016827:CD8 Antigens; D051917:Leukosialin; C465014:SPN protein, human; D012795:Sialoglycoproteins; D020148:Butyric Acid; D005700:Galactosyltransferases; D001374:Azacitidine