Glycosyl phosphatidylinositol (GPI)-anchored molecules and the pathogenesis of paroxysmal nocturnal hemoglobinuria (original) (raw)
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Glycosyl phosphatidylinositol-linked blood group antigens and paroxysmal nocturnal hemoglobinuria
Transfusion Clinique et Biologique, 1995
Human erythrocyte cell surface molecules that are attached to the cell membrane by glycosyl-phosphatidylinositol (GPI) anchors include the complement regulatory proteins decay accelarating factor (DAF, CD55) and membrane inhibitor of reactive 1ysis (MIRL, CD59), as well as the proteins that bear the Cartwright, Dombrock, and JMH blood group antigens. The acquired hematopoietic stem cell disorder paroxysmal nocturnal hemoglobinuria {PNH) results from the absence or marked deficiency in expression of GPI-anchored proteins in affected hematopoietic cells. PNH usually if not always results from a somatic mutation of an X-linked gene called PIG-A; the product of the PIG-A gene is a glycosyl transferase necessary for construction * This review contains material extracted from previously published reviews by the author and updated with the addition of recently acquired information.
Blood, 1999
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have one or a few clones of mutant hematopoietic stem cells defective in glycosylphosphatidylinositol (GPI) synthesis as a result of somatic mutation in the X-linked gene PIG-A. The mutant stem cell clone dominates hematopoiesis by a mechanism that is unclear. To test whether a lack of multiple GPI-anchored proteins results in dysregulation and expansion of stem cells, we generated mice in which GPI-anchor negative cells are present only in the hematopoietic system. We transplanted lethally irradiated mice with female fetal liver cells bearing one allele of the Piga gene disrupted by conditional gene targeting. Because of the X-chromosome inactivation, a significant fraction of the hematopoietic stem cells in fetal livers was GPI-anchor negative. In the transplanted mice, cells of all hematopoietic lineages contained GPI-anchor negative cells. The percentage of GPI-anchor negative cells was much higher in T lymphocytes includin...
Proceedings of the National Academy of Sciences, 1993
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder arising in a multipotent hemopoietic stem cell. PNH manifests clinically with intravascular hemolysis resulting from an increased sensitivity of the red cells belonging to the PNH clone to complement-mediated lysis. Numerous studies have shown that surface proteins anchored to the membrane via a glycosylphosphatidylinositol (GPI) anchor (including proteins protecting the cell from complement) are deficient on the cells of the PNH clone, leading to the notion that GPI-anchor biosynthesis may be abnormal in these cells. To investigate the biochemical defect underlying PNH we have used lymphoblastoid cell lines (LCLs) with the PNH phenotype obtained by Epstein-Barr virus immortalization of lymphocytes from nine patients with PNH. By labeling cells with myo-[3H]inositol we have found that PNH LCLs produce phosphatidylinositol normally. By contrast, PNH LCLs fail to incorporate [3H]mannose into GPI anchor precursors. When cel...
The Hematology Journal, 2000
The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as t o whether these two disorders are different forms of the same disease. We compared two groups of patients with respect t o cytogenetic features, glycosylphosphatidylinositol (GPII-linked protein expression, protein C/ protein Slthrombomodulinlantithrombin 111 activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used t o study GPI-linked protein expression (CD14 [on monocytesl, CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, 0 5 8 , and CD59 [on erythrocytesl) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow-cytometric analysis. Six of 12 patients with A A , who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis andlor hemolytic anemia. Cytogenetic features were normal in all but t w o patients. Proteins C and S, thrombomodulin, and antithrombin 111 levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% t o 98% of the cells and CD14 in 7696 t o 100Y0. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, re-CQUIRED APLASTIC ANEMIA (AA) is a heterogeneous disease, in which several pathophysiologic factors are involved.' In contrast to patients who undergo bone marrow transplantation (BMT), those who are successfully treated with immunosuppressive therapy (IST) are at risk for subsequently developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndromes, and acute myeloid l e~k e m i a .~.~ D e novo PNHh-' is an acquired clonal disorderY"" characterized by complement-mediated hemolysis and the expansion of affected cells of various hematopoietic lineages. The most typical manifestation of PNH is intravascular hemolysis due to abnormal sensitivity of red blood cells
Oman Medical Journal, 2022
Paroxysmal Nocturnal haemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disorder characterized by decreased surface expression of glycosyl phosphatidyl inositol (GPI)-anchored proteins on the cell membrane. The core mechanism held responsible is somatic mutations in phosphatidylinositol glycan class A (PIG-A) gene, mapping on the short (p) arm of the X chromosome which encodes
Journal of cellular and molecular medicine, 2015
The glycolipid glycosylphosphatidylinositol anchor (GPI-A) plays an important role in lipid raft formation, which is required for proper expression on the cell surface of two inhibitors of the complement cascade, CD55 and CD59. The absence of these markers from the surface of blood cells, including erythrocytes, makes the cells susceptible to complement lysis, as seen in patients suffering from paroxysmal nocturnal haemoglobinuria (PNH). However, the explanation for why PNH-affected hematopoietic stem/progenitor cells (HSPCs) expand over time in BM is still unclear. Here, we propose an explanation for this phenomenon and provide evidence that a defect in lipid raft formation in HSPCs leads to defective CXCR4- and VLA-4-mediated retention of these cells in BM. In support of this possibility, BM-isolated CD34(+) cells from PNH patients show a defect in the incorporation of CXCR4 and VLA-4 into membrane lipid rafts, respond weakly to SDF-1 stimulation, and show defective adhesion to fi...
Recent insights into the pathophysiology of paroxysmal nocturnal hemoglobinuria
Medical science monitor: international medical journal of experimental and clinical research
Paroxysmal nocturnal hemoglobinuria (PNH) is a unique clonal stem cell disorder characterized by intravascular hemolysis, thrombotic events and bone marrow failure. There has been accelerated progress in understanding the mechanisms underlying the clinical features of the disease over the last decade. The development of PNH requires not only a somatic mutation of the phospatidylinositol glycan complementation class A (PIG-A) gene, but also a survival advantage of the PNH clone ('dual pathogenesis' theory). There is increasing evidence that negative selection against the non-mutated cells rather than positive selection of the PIG-A gene mutant cells is responsible for the dominance of the PNH clone. In this review, we summarize the important advances in the understanding of PNH, but we also concentrate on the presence of PNH clones in other hematological disorders, including aplastic anemia (AA), myelodysplastic syndromes (MDS), acute leukemias, and myeloproliferative and lymphoproliferative syndromes. The fuller comprehension of the pathophysiology of PNH may have wider implications than for PNH itself, as indicated by the presence of PNH clones in these hematological malignancies, and by the therapeutic implications of this fact, as already described in patients with AA and MDS. key words: paroxysmal nocturnal hemoglobinuria • aplastic anemia • myeloproliferative disorders • lymphoproliferative syndromes • myelodysplastic syndromes • acute leukemia Full-text PDF: RA162 Med Sci Monit, 2003; 9(7): RA161-172 Review Article RA163 Med Sci Monit, 2003; 9(7): RA161-172 Meletis J et al -Pathophysiology of paroxysmal nocturnal hemoglobinuria RA PNH and thrombosis; and finally (5) the association between PNH and bone marrow failure [27]. The first three problems have already been solved.
Cytometry Part B: Clinical Cytometry, 2012
Background. Paroxysmal nocturnal hemoglobinuria (PNH) is a unique disorder caused by a PIG-A gene mutation in a stem cell clone. Its clinical picture can sometimes make challenging the distinction from other disorders, and especially from myelodysplastic syndromes (MDS), since both diseases correlate with cytopenias and morphological abnormalities of bone marrow (BM) cells. Recently, flow cytometry (FC) has been proposed to integrate the morphologic assessment of BM dysplasia, and thus to improve the diagnostics of MDS. Methods. In the present study, we have analyzed systematically FC data resulting from the study of BM cells from patients with PNH and MDS. Results. Our data demonstrated abnormalities in PNH beyond the deficiency of glycosylphosphatidylinositol-linked proteins and the application of a systematic approach allowed us to separate effectively MDS and PNH in a cluster analysis and to highlight disease-specific abnormalities. Indeed, the parallel evaluation of some key parameters, i.e. patterns of expression of CD45 and CD10, provided information with practical diagnostic usefulness in the distinction between PNH and MDS. Moreover, the hypoexpression of CD36 that we observed on monocytes might be related to the thrombotic tendency in PNH. Conclusions. We investigated systematically the phenotypic profile of BM cells from patients with PNH; our data provide useful antigenic patterns to solve between PNH and MDS, sometimes morphologically overlapping. Moreover, some PNH-related phenotypic changes might be involved in the physiopathology of the disease and further studies addressing this issue are warranted. V