The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria

Karadimitris, Anastasios; Luzzatto, Lucio

doi:10.1038/sj.leu.2402180

Cited by 66 publications

(42 citation statements)

References 32 publications

(27 reference statements)

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“…Although we cannot rule out that this happens in exceptional cases, it is evident that PIG-A mutations do not necessarily lead to inexorable clonal expansion, even when they are associated with visible chromosomal abnormalities. 17 Our clinical findings are instead most consistent with the model of immunological selection in favor of PNH cells, 16,29 which also explains the presence of multiple PNH clones in some patients. 30,31 Auto-immune processes often wax and wane; if autoimmune selection in favor of the PNH clone wanes, one would expect to see clones that may be large but are no longer expanding, as we have observed.…”

Section: Pathophysiologysupporting

confidence: 80%

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

et al. 2002

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PNH is characterized by expansion of one or more stem cell clones with a PIG-A mutation, which causes a severe deficiency in the expression of glycosylphosphatidylinositol (GPI)-anchored proteins. There is evidence that the expansion of PIG-A mutant clones is concomitant with negative selection against PIG-A wild-type stem cells by an aplastic marrow environment. We studied 36 patients longitudinally by serial flow cytometry, and we determined the proportion of PNH red cells and granulocytes over a period of 1-6 years. We observed expansion of the PNH blood cell population(s) (at a rate of over 5% per year) in 12 out of 36 patients; in all other patients the PNH cell population either regressed or remained stable. The dynamics of the PNH cell population could not be predicted by clinical or hematologic parameters at presentation. These data indicate that in most cases the PNH cell expansion has already run its course by the time of diagnosis. In addition, since in most cases no further expansion takes place, we can infer that the tendency to overgrow normal cells is not an intrinsic property of the PNH clone.

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Section: Pathophysiologysupporting

confidence: 80%

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

et al. 2002

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“…The total amount of CD34þ cells on global cellularity was reduced. This finding has already been reported [23] and is not surprising taking into consideration the autoimmune-mediated attack that provides a relative advantage to PNH clone [24]. The proportions among CD34þ subpopulations were also affected: B lymphoid precursors were not detectable in the majority of our cases and the mean percentage of CD34þ/CD38þ fraction was higher than in normal BM.…”

Section: Discussionsupporting

confidence: 86%

A systematic analysis of bone marrow cells by flow cytometry defines a specific phenotypic profile beyond GPI deficiency in paroxysmal nocturnal hemoglobinuria

Mannelli¹,

Bencini²,

Peruzzi³

et al. 2012

Cytometry Part B Clinical

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Background. Paroxysmal nocturnal hemoglobinuria (PNH) is a unique disorder caused by a PIG-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 C 2012 International Clinical Cytometry Society

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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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The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria

Cited by 66 publications

References 32 publications

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

A systematic analysis of bone marrow cells by flow cytometry defines a specific phenotypic profile beyond GPI deficiency in paroxysmal nocturnal hemoglobinuria

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

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