Inherited Complete Deficiency of 20-Kilodalton Homologous Restriction Factor (CD59) as a Cause of Paroxysmal Nocturnal Hemoglobinuria

Yamashina, Manabu; Ueda, Etsuko; Kinoshita, Tsuguki; Takami, T; Ojima, Akitsugu; Ono, Hiromasa; Tanaka, Hiroshi; Kondo, Naomi; Orii, Tadao; Okada, Noriko; Okada, Hidechika; Inoue, Kôzô; Kitani, Teruo

doi:10.1056/nejm199010253231707

Cited by 340 publications

(174 citation statements)

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“…In PNH, a mutation in a hematopoietic stem cell gives rise to a clone of blood cells that lack glycolipid-anchored molecules and are highly susceptible to complement-mediated lysis in vitro and in vivo. PNH is an acquired disorder; however, in a single isolated case of hereditary CD59 deficiency, a PNH-like pathology was described (4,5). In contrast to humans, mice have two CD59 genes encoded on chromosome 2: mCd59a and mCd59b.…”

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confidence: 99%

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Turnberg¹,

Botto²,

Warren³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. CD59 is a complement regulatory protein that inhibits the terminal part of the complement system, the membrane attack complex (MAC), a mediator of renal injury. Mice deficient in the Cd59a gene (mCd59aϪ/Ϫ) were used to investigate the role of CD59 in experimentally induced accelerated nephrotoxic nephritis, a model of immune complex-mediated glomerulonephritis. After accelerated nephrotoxic nephritis was induced by administration of sheep nephrotoxic globulin, mCd59aϪ/Ϫ mice and strain-matched controls on two genetic backgrounds, 129/Sv ϫ C57BL/6 and 129/Sv, were examined. For both, mCd59aϪ/Ϫ mice developed significantly greater glomerular cellularity than wild-type (WT) mice at day 5 after administration. At day 10 post-administration, mCd59aϪ/Ϫ mice exhibited more glomerular thrombosis than WT mice (thrombosis score, 1.8 [range, 1.4 to 4.0] versus 0.8 [range, 0.2 to 1.5] quadrants thrombosed per glomerulus, respectively; P ϭ 0.0006). In the majority of experiments, mCd59aϪ/Ϫ mice also had significantly more proteinuria than controls; however, there was no difference in serum creatinine or albumin. Quantitative immunofluorescence of kidney sections revealed significantly more C9 (as a marker of MAC) deposition within glomeruli of mCd59aϪ/Ϫ mice than WT controls (P Ͻ 0.001). There was no difference in deposition of C3 and sheep IgG between the two experimental groups. The lack of CD59a, by allowing unregulated MAC deposition, exacerbates the renal injury in this model of immune complex-mediated glomerulonephritis.

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mentioning

confidence: 99%

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Turnberg¹,

Botto²,

Warren³

et al. 2003

Journal of the American Society of Nephrology

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“…44 The sole described case of total CD59 deficiency presented in childhood with symptoms compatible with PNH, but with an unexplained history of neurological disease. 45 No follow-up of this patient has been reported, making impossible any conclusions regarding the effects of CD59 deficiency in the brain in humans. It is possible that chronic activation of C and formation of MAC in the brain in MS may deplete reserves of CD59, a suicide inhibitor consumed during interaction with MAC, resulting in a state of functional deficiency in areas of pathology.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis

et al. 2003

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There is a growing body of evidence implicating complement and, in particular, the terminal pathway (membrane attack complex; MAC) in inducing demyelination in multiple sclerosis and experimental allergic encephalomyelitis. In this paper, we examined the disease course and pathological changes in mice deficient in the major regulator of MAC assembly, CD59a, during the course of acute experimental allergic encephalomyelitis induced by immunisation with recombinant myelin oligodendrocyte glycoprotein. Disease incidence and severity were significantly increased in CD59a-deficient mice. The extent of inflammation, demyelination and axonal injury were assessed in spinal cord cross-sections from CD59a-deficient and control mice, and all these parameters were enhanced in the absence of CD59a. Areas of myelin loss and axonal damage in CD59a-deficient mice were associated with deposits of MAC, firmly implicating MAC as a cause of the observed injury. These findings are relevant to some types of human demyelination, where abundant deposits of MAC are found in association with pathology.

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“…Although DAF was completely absent from all circulating cells (Reid et al, 1991), none of the propositi had symptoms suggestive of paroxysmal nocturnal hemoglobinuria (PNH), a complement-mediated hemolytic disease due to the deficiency of complement regulators such as CD59 and DAF; 2) a mDAF knockout mouse did not show any evidence of intravascular hemolysis (Sun et al, 1999); and 3) an index case report from Japan described a man who had a global deficiency of hCD59 due to single nucleotide deletions in the CD59 gene, which placed the gene product out of frame and introduced a premature stop codon. This subject expressed a severe PNH phenotype from the unusually young age of thirteen and also had a stroke that left him with permanent neurological damage (Yamashina et al, 1990). Not only does the Cd59 knockout out mouse exhibit a full PNH-like anemia as well as platelet activation, but it also exhibits progressive loss of fertility (Holt et al, 2001;Qin et al, 2009;Qin et al, 2003).…”

Section: Anti-mac Regulator Cd59mentioning

confidence: 99%