Paroxysmal Nocturnal Hemoglobinuria and Glycosyl Phosphatidylinositol Anchored Proteins That Regulate Complement

Parker, CJ

doi:10.1111/j.1365-2249.1991.tb06205.x

Cited by 14 publications

(3 citation statements)

References 62 publications

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“…The mutation results in the reduction or complete absence of the GPI-anchored complement regulatory proteins CD55 and CD59, which renders the cells sensitive to complement-mediated destruction (Rother et al , 2005; Kelly et al , 2009). All blood cells are susceptible to complement-mediated attack, although red blood cells are the most susceptible to lysis (Parker, 1991; Pu & Brodsky, 2011). …”

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confidence: 99%

Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

et al. 2013

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Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.

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confidence: 99%

Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

et al. 2013

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“…CD59 (MIRL) was eventually isolated as a result of a series of events that demonstrates how closely intertwined are the studies of erythrocyte complement regulation with those of paroxysmal nocturnal hemoglobinuria (PNH; reviewed in Parker, 1991). PNH is an uncommon type of hemolytic anemia that arises as a consequence of the abnormal sensitivity of the erythrocytes to complement-mediated lysis (reviewed in Rosse, 1990).…”

Section: Identification and Isolation Of Cd59mentioning

confidence: 99%

Isolation and Functional Assay of the Membrane Complement Inhibitors CD55 (DAF) and CD59 (MIRL)

Parker

1994

CP in Immunology

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The complement system is the primary effector of humoral immunity. Because of its enormous destructive capacity, mechanisms for confining the activity of the system to the desired target and elaborate safeguards for protecting self against complement-mediated injury have evolved. Human cells, particularly those found at sites of inflammation (e.g., hematopoietic and endothelial cells), express highly specialized membrane constituents that act independently or in concert with plasma regulatory proteins to inhibit the functional activity of complement. Decay-accelerating factor (DAF), or CD55, directly inhibits the formation and stability of the amplification C3 and C5 convertases of both the classical and the alternative pathways. Failure of a cell to regulate the amplification C3 and C5 convertases allows the generation of the potentially cytolytic membrane attack complex (MAC), or C5b-9 (consisting of the complement components C5b, C6, C7, C8, and C9). The primary cellular regulator of the MAC is the membrane inhibitor of reactive lysis (MIRL), or CD59, which restricts complement-mediated lysis by blocking assembly of the MAC (primarily at the stage of C9 binding and polymerization). This unit provides a basic protocol for isolating CD55 and CD59, along with two support protocols describing separate functional assays for CD59 and CD55.

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“…5 In the early sixties of the last century it was confirmed that in PNH patients, whereas there was nothing wrong with complement as such, there was a discrete population of red cells exquisitely sensitive to complement. 6 The discovery that PNH is a clonal disease, 7 of DAF (CD55) 8 and MIRL (CD59), 9 of the fact that they are GPI-linked proteins, 10 and that GPI is lacking in PNH red cells consequent on a somatic mutation of PIGA 11,12 are part of a more recent history. Thus, we have known for some decades that, although complement activation is not causative of PNH, it is responsible for many of its clinical manifestations.…”

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confidence: 99%

Closing remarks

Luzzatto

2022

American J Hematol

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Paroxysmal Nocturnal Hemoglobinuria and Glycosyl Phosphatidylinositol Anchored Proteins That Regulate Complement

Cited by 14 publications

References 62 publications

Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

Isolation and Functional Assay of the Membrane Complement Inhibitors CD55 (DAF) and CD59 (MIRL)

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