Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why? Why?”

Young, Neal S.; Maciejewski, Jaroslaw P.

doi:10.1172/jci11002

Cited by 91 publications

(69 citation statements)

References 24 publications

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“…4 It appears unlikely that an intrinsic difference of PIG-A mutated clone is sufficient to account for selective expansion of a PNH clone. 3,[33][34][35] The four hemolytic PNH patients reported here may be extreme examples in the setting of hematopoietic failure of an immune pathophysiology that may be present in a more subtle form in all PNH and possibly also in AA. In a continuum of antigen-driven clonal responses in immune-mediated bone marrow failure syndromes, 23 these hemolytic PNH patients would be very close to the pole represented by LGL-leukemia.…”

Section: Molecular Analysis Of Lgl-like Expansions In Pnh Patientsmentioning

confidence: 83%

“…Our data are compatible with a pathogenic model of PNH in which extrinsic factors confer a selective advantage to GPI-APdeficient hematopoiesis. 3 Variables determining the relative manifestations of marrow failure vs T-cell proliferation likely include the nature of the specific antigen(s) driving the immune pathophysiology, the efficiency of hematopoietic target cell killing, and biological features of the pathogenic T-cell clone providing for growth or survival advantages. Additional intrinsic features of mutant PNH clone may themselves also affect hematopoietic function.…”

Section: Molecular Analysis Of Lgl-like Expansions In Pnh Patientsmentioning

confidence: 99%

“…Intravascular hemolysis results from failure of complement inactivation by CD59, missing from the surface of GPI-AP-deficient erythrocytes. 3 However, the pathogenesis of other cardinal features of PNH, such as the propensity to venous thrombosis and bone marrow failure, remains unclear. 3,4 Moreover, expansion of a PNH clone is not the simple result of the mutational event, as PIG-A-mutant cells exist in small numbers in normal individuals, and murine 'knock-out' animals do not show inexorable proliferation of aberrant clones.…”

Section: Introductionmentioning

confidence: 99%

“…3 However, the pathogenesis of other cardinal features of PNH, such as the propensity to venous thrombosis and bone marrow failure, remains unclear. 3,4 Moreover, expansion of a PNH clone is not the simple result of the mutational event, as PIG-A-mutant cells exist in small numbers in normal individuals, and murine 'knock-out' animals do not show inexorable proliferation of aberrant clones. Clinical overlap with immunemediated aplastic anemia (AA) has suggested the hypothesis of an autoimmune pathophysiology of PNH.…”

Section: Introductionmentioning

confidence: 99%

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Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

Risitano

Maciejewski²,

Muranski

et al. 2005

Leukemia

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Section: Molecular Analysis Of Lgl-like Expansions In Pnh Patientsmentioning

confidence: 83%

Section: Molecular Analysis Of Lgl-like Expansions In Pnh Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

Risitano

Maciejewski²,

Muranski

et al. 2005

Leukemia

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“…This would result, in PNH cells, in the accumulation of unprocessed proteins which, in association with chaperones residing in the endoplasmic reticulum, are transferred to the cytoplasm where they are degraded. 22 Thus, although it has been suggested that PNH cells may present a critical epitope less efficiently than GPI + cells, 23,24 there is no experimental evidence to support this notion. Therefore, peptides from GPI-linked proteins do not seem at the moment good candidate targets either.…”

Section: The Target Of Autoaggressive T Cells Is An Epitope Derived Fmentioning

confidence: 99%

The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria

Karadimitris

Luzzatto

2001

Leukemia

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Paroxysmal nocturnal haemoglobinuria (PNH) is a unique disorder characterised by the triad of intravascular haemolysis, thrombosis and bone marrow failure. In the early seventies it was shown that PNH is a clonal disease; and in the nineties the molecular basis of the PNH abnormality was elucidated. However, what makes a PNH clone expand is still not known. Here, we suggest that this is due to somatic cell selection, resulting from the presence in the patient of autoreactive T cells that target glycosylphosphatidylinositol (GPI) in the context of an MHC-like molecule on the surface of haemopoietic stem cells. PNH cells would escape damage precisely because they have lost most or all of their ability to produce GPI. Leukemia (2001) 15, 1148-1152.

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Paroxysmal Nocturnal Hemoglobinuria

Kinoshita

2012

Encyclopedia of Life Sciences

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Paroxysmal nocturnal hemoglobinuria is a peculiar acquired clonal genetic disease caused by somatic mutation of the X‐linked PIGA gene in a hematopoietic stem cell. Loss‐of‐function mutation in PIGA gene causes a lack or a decreased biosynthesis of glycosylphosphatidylinositol (GPI), which in turn results in a complete or a partial deficiency in the cell surface expression of GPI‐anchored proteins, such as CD59 and CD55. The PIGA ‐mutant stem cell clone becomes dominant in hematopoiesis due to an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics after additional genetic change(s) such that it causes ectopic expression of HMGA2 gene known to cause benign tumours. Mutant red blood cells lacking CD59 and CD55 are highly sensitive to complement and are lysed upon activation of complement during infection and other events, resulting in haemolytic anemia and hemoglobinuria. A humanised monoclonal antibody against fifth component of complement C5 that inhibits activation of C5 is now in clinical use to prevent intravascular haemolysis. Key Concepts: Paroxysmal nocturnal hemoglobinuria is an acquired genetic disease due to somatic mutation in the X‐linked PIGA gene that occurs in the hematopoietic stem cell. Loss‐of‐function somatic PIGA mutation causes a defective biosynthesis of glycosylphosphatidylinositol (GPI). The defective biosynthesis in GPI that anchors many proteins onto the plasma membrane, leads to defective cell surface expression of GPI‐anchored proteins. The PIGA ‐defective mutant clone expands and dominates hematopoietic cells in bone marrow and the peripheral blood. The clonal expansion is mediated by an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics. A lack of GPI‐anchored proteins makes red blood cells sensitive to homologous complement due to a loss of complement regulators, CD59 and CD55. Complement‐mediated haemolysis of GPI‐deficient red blood cells results in haemolytic anemia and hemoglobinuria. A humanised anti‐C5 monoclonal antibody is in clinical use to prevent intravascular haemolysis.

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Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why? Why?”

Cited by 91 publications

References 24 publications

Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria

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