Expression of cryptantigen Th on paroxysmal nocturnal hemoglobinuria erythrocytes in association with a hemolytic exacerbation.

Nakakuma, Hideki; Hidaka, Masaaki; Nagakura, Shoichi; Nishimura, Y; Iwamoto, Norihiro; Horikawa, Kiyoshi; Kawaguchi, Tatsuya; Kagimoto, Tadashi; Takatsuki, Kiyoshi

doi:10.1172/jci118021

Cited by 21 publications

(5 citation statements)

References 25 publications

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“…11 A mechanism of infection-associated precipitation of hemolysis also has been shown. 12 Proclivity to thrombosis is also attributable to PIG-A mutations, but a molecular mechanism has not been found. 13,14 Despite rapid progress in understanding PNH pathophysiology, the etiology and the mechanism by which a PNH clone expands are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Decreased susceptibility of leukemic cells with PIG-Amutation to natural killer cells in vitro

Nagakura

Ishihara

Dunn

et al. 2002

Blood

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The cloning of the PIG-A gene has facilitated the unraveling of the complex pathophysiology of paroxysmal nocturnal hemoglobinuria (PNH). Of current major concern is the mechanism by which a PNH clone expands. Many reports have suggested that an immune mechanism operates to cause bone marrow failure in some patients with PNH, aplastic anemia, and myelodysplastic syndromes. Because blood cells of PNH phenotype are often found in patients with these marrow diseases, one hypothesis is that the PNH clone escapes immune attack, producing a survival advantage by immunoselection. To test this hypothesis, we examined the sensitivity of blood cells, with or without PIG-A mutations, to killing by natural killer (NK) cells, using 51 Cr-release assay in vitro. To both peripheral blood and cultured NK cells, PIG-A mutant cells prepared from myeloid and lymphoid leukemic cell lines were less susceptible than their control counterparts (reverted from the mutant cells by transfection with a PIG-A cDNA). NK activity was completely abolished with concanamycin A and by calcium chelation, indicating that killing was perforin-dependent. There were no differences in major histocompatibility (MHC) class I expression or sensitivity to either purified perforin or to interleukin-2-activated NK cells between PIG-A mutant and control cells. From these results, we infer that PIG-A mutant cells lack molecules needed for NK activation or to trigger perforin-mediated killing. Our experiments suggest that PIG-A mutations confer a relative survival advantage to a PNH clone, contributing to selective expansion of these cells in the set- IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal stem cell disorder that manifests clinically as intravascular hemolysis, venous thrombosis, frequent episodes of infection, and rare leukemic conversion. 1,2 In addition, PNH is often a bone marrow (BM) failure syndrome, strongly related to aplastic anemia and the myelodysplastic syndromes (MDSs). 3,4 All 3 processes may occur in a single patient. 5,6 Among the clinical manifestations, the molecular events leading to hemolysis have been elucidated 7-9 and the responsible gene PIG-A has been cloned. 10 PNH cells with PIG-A mutation do not produce glycosylphosphatidylinositol (GPI) and lack cell surface expression of a large family of proteins that utilize GPI to localize in the plasma membrane. 10 Therefore, PNH cells, deficient in complement regulatory GPI-linked proteins such as decay-accelerating factor (DAF) and CD59, undergo complement-mediated hemolysis characteristic of PNH. 11 A mechanism of infection-associated precipitation of hemolysis also has been shown. 12 Proclivity to thrombosis is also attributable to PIG-A mutations, but a molecular mechanism has not been found. 13,14 Despite rapid progress in understanding PNH pathophysiology, the etiology and the mechanism by which a PNH clone expands are still unknown. 15 Murine pig-a knockout models have shown that clonal expansion of PNH cells does not follow on the presence of the ...

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Section: Introductionmentioning

confidence: 99%

Decreased susceptibility of leukemic cells with PIG-Amutation to natural killer cells in vitro

Nagakura

Ishihara

Dunn

et al. 2002

Blood

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“…Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia.…”

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Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder of clonal nature characterized by intravascular hemolysis, venous thrombosis, bone marrow (BM) dysfunction, and infrequent development of leukemia. [1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59. PNH cells are then vulnerable to autologous complement. For example, PNH erythrocytes undergo complement-mediated hemolysis. Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure. 1,12,14,15 Of interest, combination therapy with antithymocyte globulin and cyclosporine A, these immunosuppressants having individual target spectra, 16,17 gives better results than therapy with each 1 of the 2 immunosuppressants. 12,18 In general, both cytotoxic T lymphocytes (CTLs) of adaptive immunity and natural killer (NK) cells of innate immunity operate in combination rather than independently. [19][20][21][22] It is then conceivable that both cytotoxic cells exert critical roles in BM injury, 12,[23][24][25][26] although real features of the autoimmunity have not been delineated.The marked progress in understanding of PNH pathophysiology evokes the next concern about the etiology of PNH, and the mechanisms of both selective expansion of PNH clones 27 and development of leukemia. 28 Above all, we have focused on the expansion of affected cells to mani...

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“…A gene responsible for the membrane defect, PIG‐A , has been cloned ( Miyata et al , 1993 ; Takeda et al , 1993 ). Moreover, a possible mechanism of complement activation in infection‐associated haemolytic precipitation has been shown ( Nakakuma et al , 1995a ). Advances in research on PNH haemolysis have markedly improved the methods of PNH diagnosis, i.e.…”

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Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes

et al. 1998

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Summary. Among acquired stem cell disorders, pathological links between myelodysplastic syndromes (MDS) and aplastic anaemia (AA), and paroxysmal nocturnal haemoglobinuria (PNH) and AA, have been often described, whereas the relationship between MDS and PNH is still unclear. We analysed blood cells of patients with MDS to determine the incidence of the PNH clone, and analysed the PIG-A gene to find mutations characteristic of the PNH clone in MDS. In four (10%) of 40 patients with MDS, flow cytometry showed affected erythrocytes and granulocytes negative for decayaccelerating factor (DAF) and CD59. The population of affected erythrocytes was smaller in MDS patients with PNH clone (MDS/PNH) than in patients with de novo PNH, and haemolysis was milder in the MDS/PNH patients. PIG-A mutations were found in granulocytes of all patients with MDS/PNH. In type and site, the PIG-A mutations were heterogenous, similar to that observed in de novo PNH; i.e. no mutation specific to MDS/PNH was identified. Of note, three of four patients with MDS/PNH each had two PNH clones with different PIG-A mutations, suggesting that PIG-A is mutable in patients with MDS/PNH. In a MDS/PNH patient with trisomy 8, FISH detected a distinct karyotype in a portion of granulocytes with PNH phenotype, indicating that PNH and MDS partly shared affected cells. Thus, MDS predisposes to PNH by creating conditions favourable to the genesis of PNH clone. Considering the increasing prevalence and incidence of MDS, these disorders could be useful for investigating the mechanism by which PIG-A mutation is induced.

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Expression of cryptantigen Th on paroxysmal nocturnal hemoglobinuria erythrocytes in association with a hemolytic exacerbation.

Cited by 21 publications

References 25 publications

Decreased susceptibility of leukemic cells with PIG-Amutation to natural killer cells in vitro

Decreased susceptibility of leukemic cells with PIG-Amutation to natural killer cells in vitro

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes

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