Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria.

Takahashi, Minoru; Takeda, Junji; Hirose, Shinichi; Hyman, Robert; Inoue, Norimitsu; Miyata, Toshio; Ueda, Etsuko; Kitani, Teruo; Medof, M. Edward; Kinoshita, Taroh

doi:10.1084/jem.177.2.517

Cited by 170 publications

(72 citation statements)

References 24 publications

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“…PNH is a hematologic disorder characterized by bone marrow failure, thrombophilia, complement-mediated intravascular hemolysis, and hemoglobinuria. It is caused by a clonal expansion of RBC precursors that contain a mutation in the X-linked phosphatidylinositol glycan anchor biosynthesis, class A gene (PIGA) that encodes for a protein involved in GPI anchor synthesis (80). DAF and CD59 are GPI-anchored molecules that require posttranslational addition of GPI anchors to guide them to cell surfaces.…”

Section: Kidney Injury Mediated By Serum Complement In the Absence Ofmentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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Section: Kidney Injury Mediated By Serum Complement In the Absence Ofmentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

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“…Impaired synthesis of GPI anchor results in the deficiency of such proteins from the red cell membrane. Studies with abnormal lymphoid cell lines established from PNH patients indicate that the first step of GPI anchor synthesis is defective [20,21]. The genes responsible for this particular step, called PIG-A, PIG-C and PIG-H, have been cloned and characterized [22,23].…”

Section: Pnhmentioning

confidence: 99%

Hematopoietic progenitor cells in the blood and bone marrow in various hematologic disorders

et al. 2009

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Hematopoietic progenitor cells are present in the blood and the bone marrow. Changes in the numbers of hematopoietic progenitor cells reflect alteration of pluripotent stem cells. We discus such changes in common hematologic diseases including aplastic anemia, paroxysmal nocturnal hemoglobinnria (PNl3) and thalassemia, In aplastic anemia, the numbers of burst forming unitserythroid (BFU-E) and colony-forming units-granulwybmacrophage (Cmr-GM) are much decreased; the decrease stiU exists &r recovery from therapy. In PNH, the numbers of progenitor cells are low, even in the presence of marrow hypercellnlarity. In thalmmia, the numbers of progenitor cells are niuch increased; more pronounced in splenectomized patients. Stem Ceh 1998;16(~u~pl1):123-128

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“…The Pig-A gene, located on the X-chromosome, codes for a catalytic subunit of the N-acetylglucosamine transferase complex that is involved in an early step of glycosylphosphatidyl inositol (GPI) anchor synthesis (Takahashi et al, 1993). The Pig-A gene mutation assay is a new in vivo mutation test that may become an alternative to the transgenic rodent gene mutation assay..…”

Section: A New In Vivo Test For Gene Mutation: the Pig-a Mutation Assaymentioning

confidence: 99%

Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment

2011

EFS2

298

136

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The Scientific Committee reviewed the current state-of-the-science on genotoxicity testing and provided a commentary and recommendations on genotoxicity testing strategies. A step-wise approach is recommended for the generation and evaluation of data on genotoxic potential, beginning with a basic battery of in vitro tests, comprising a bacterial reverse mutation assay and an in vitro micronucleus assay. Consideration should be given to whether specific features of the test substance might require substitution of one or more of the recommended in vitro tests by other in vitro or in vivo tests in the basic battery. In the event of negative in vitro results, it can be concluded that the substance has no genotoxic potential. In case of inconclusive, contradictory or equivocal results, it may be appropriate to conduct further testing in vitro. In case of positive in vitro results, review of the available relevant data on the test substance and, where necessary, an appropriate in vivo study to assess whether the genotoxic potential observed in vitro is expressed in vivo is recommended. Suitable in vivo tests are the mammalian erythrocyte micronucleus test, transgenic rodent assay, and Comet assay. The approach to in vivo testing should be step-wise. If the first in vivo test is positive, no further testing is necessary and the substance should be considered as an in vivo genotoxin. If the test is negative, it may be possible to conclude that the substance is not an in vivo genotoxin. However, in some cases, a second in vivo test may be necessary (e.g. if the first test is negative but more than one endpoint in the in vitro tests are positive, an in vivo test on a second endpoint may be necessary). The combination of assessing different endpoints in different tissues in the same animal in vivo should also be considered.

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Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria.

Cited by 170 publications

References 24 publications

Molecules Great and Small

Molecules Great and Small

Hematopoietic progenitor cells in the blood and bone marrow in various hematologic disorders

Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment

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