Primary and Secondary CD59 Deficiency (original) (raw)
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Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria
Blood, 2001
The glycolipid-anchored glycoprotein CD59 inhibits assembly of the lytic membrane attack complex of complement by incorporation into the forming complex. Absence of CD59 and other glycolipid-anchored molecules on circulating cells in the human hemolytic disorder paroxysmal nocturnal hemoglobinuria is associated with intravascular hemolysis and thrombosis. To examine the role of CD59 in protecting host tissues in health and disease, CD59-deficient (CD59−/−) mice were produced by gene targeting in embryonic stem cells. Absence of CD59 was confirmed by staining cells and tissues with specific antibody. Despite the complete absence of CD59, mice were healthy and fertile. Erythrocytes in vitro displayed increased susceptibility to complement and were positive in an acidified serum lysis test. Despite this, CD59−/− mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from CD59−/− mice contained increased amounts of ...
Blood, 2006
Paroxysmal nocturnal hemoglobinuria (PNH) results from the expansion of a hematopoietic clone that is deficient in glycosylphosphatidylinositol-anchored molecules. PNH is characterized by chronic hemolysis with acute exacerbations due to the uncontrolled activity of complement on PNH cells, which lack the inhibitor of homologous complement, CD59. Symptoms include severe fatigue, hemoglobinuria, esophageal spasm, erec-tile dysfunction, and thrombosis. We report the use of a novel synthetically modified recombinant human CD59, rhCD59-P, a soluble protein that attaches to cell membranes. In vitro treatment of PNH erythrocytes with rhCD59-P resulted in levels of CD59 equivalent to normal erythrocytes and effectively protected erythrocytes from complement-mediated hemolysis. The administration of rhCD59-P to CD1 mice resulted in levels of CD59 on erythrocytes, which protected them from complement-mediated lysis. Thus, rhCD59-P corrects the CD59 deficiency in vitro and can bind to erythrocytes in an in vivo murine model, protecting the cells from the activity of human complement, and represents a potential therapeutic strategy in PNH. (Blood. 2006;107: 2131-2137)
Blood, 2012
• A novel clinical syndrome is reported which is triggered by common febrile episodes in infancy and presents with Coombs' neg hemolysis and demyelineating polyneuropathy. • A gene mutation in CD59 leading to loss of expression of CD59 on the cell surface is presented as the genetic basis for the disease. CD59 deficiency is a common finding in RBCs and WBCs in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria in which the acquired mutation in the PIGA gene leads to membrane loss of glycosylphosphatidylinositol-anchored membrane proteins, including CD59. The objective of the present study was to elucidate the molecular basis of childhood familial chronic Coombs-negative hemolysis and relapsing polyneuropathy presenting as chronic inflammatory demyelinating polyradiculoneuropathy in infants of North-African Jewish origin from 4 unrelated families. A founder mutation was searched for using homozygosity mapping followed by exome sequencing. The expression of CD59, CD55, and CD14 was examined in blood cells by flow cytometry followed by Western blot of the CD59 protein. A homozygous missense mutation, p.Cys89Tyr in CD59, was identified in all patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jewish subjects of North-African origin. The mutated protein was present in the patients' cells in reduced amounts and was undetectable on the membrane surface. Based on the results of the present study, we conclude that the Cys89Tyr mutation in CD59 is associated with a failure of proper localization of the CD59 protein in the cell surface. This mutation is manifested clinically in infancy by chronic hemolysis and relapsing peripheral demyelinating disease. (Blood. 2013;121(1):129-135)
European Journal of Immunology, 1992
Human umbilical vein endothelial cells (HUVEC) were found by Western blot analysis to express three membrane-bound C regulatory proteins, decayaccelerating factor (DAF), membrane cofactor protein (MCP) and CD59. DAF was detected on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a 70-kDa molecule under nonreducing conditions in 2 % deoxycholate extracts of HUVEC, MCP as a 63-kDa protein and CD59 as a 20-kDa molecule. Northern blot analysis revealed the presence of two species of mRNA expressed in HUVEC,which hybridized to a cDNA probe specific for DAF, with sizes of about 2.0 kb and 2.7 kb. MCP mRNA was detected at 4.2 kb and a CD59 cDNA probe hybridized with three mRNA species with sizes of about 800, 1400 and 2000 bp. DAF and CD59 were released from the surface of HUVEC by phosphatidylinositol-phospholipase C, demonstrating that both are attached to the cell membrane by means of a glycolipid anchor.The relative contribution of DAF, MCP and CD59 in regulating the sensitivity to lysis of HUVEC by autologous complement was determined by incubation of sensitized endothelial cells with F(ab'). fragment5 of polyclonal antibodies raised against these proteins. The susceptibility of sensitized cells to lysis by homologous complement was markedly increased in the presence of F(ab')z anti-CD59 and to a lesser, but significant, extent in the presence ofF(ab')z anti-DAF. F(ab')z anti-MCP did not significantly alter the susceptibility of HUVEC to complement-mediated lysis.
Molecular pathogenesis of human CD59 deficiency
Neurology Genetics
ObjectiveTo characterize all 4 mutations described for CD59 congenital deficiency.MethodsThe 4 mutations, p.Cys64Tyr, p.Asp24Val, p.Asp24Valfs*, and p.Ala16Alafs*, were described in 13 individuals with CD59 malfunction. All 13 presented with recurrent Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy, recurrent strokes, and chronic hemolysis. Here, we track the molecular consequences of the 4 mutations and their effects on CD59 expression, localization, glycosylation, degradation, secretion, and function. Mutants were cloned and inserted into plasmids to analyze their expression, localization, and functionality.ResultsImmunolabeling of myc-tagged wild-type (WT) and mutant CD59 proteins revealed cell surface expression of p.Cys64Tyr and p.Asp24Val detected with the myc antibody, but no labeling by anti-CD59 antibodies. In contrast, frameshift mutants p.Asp24Valfs* and p.Ala16Alafs* were detected only intracellularly and did not reach the cell surface. Weste...
Membrane defence against complement lysis: The structure and biological properties of CD59
Immunologic Research, 1993
The complement system is an important branch of the innate immune response, constituting a first line of defence against invading microorganisms which activate complement via both antibody-dependent and -independent mechanisms. Activation of complement leads to (a) a direct attack upon the activating cell surface by assembly of the pore-forming membrane attack complex (MAC), and (b) the generation of inflammatory mediators which target and recruit other branches of the immune system. However, uncontrolled coinplement activation can lead to widespread tissue damage in the host, since certain of the activation products, notably the fragment C3b and the C5b-7 complex, can bind nonspecifically to any nearby cell membranes. Therefore it is important that complement activation is tightly regulated. Our own cells express a number of membrane-bound control proteins which limit complement activation at the cell surface and prevent accidental complement-mediated damage. These include decay-accelerating factor, complement receptor 1 and membrane cofactor protein, all of which are active at the level of C3/C5 convertase formation. Until recently, cell surface control of MAC assembly had been attributed to a single 65-kD membrane protein called homologous restriction factor (alternatively named CS-binding protein and MAC-inhibiting protein). However a second MAC-inhibiting protein has since been discovered and it is now clear that this protein plays a major role in the control of membrane attack. This review charts the rapid progress made in elucidating the protein and gene structure, and the mechanism of action of this most recently discovered complement inhibitor, CD59. Dr. Alexandra Davies 9 1993 MRC Centre S. Karger AG, Basel Hills Road 0257-277X/93/ Cambridge CB2 2QH (UK) 0123-025852.75/0
Regulation of CD59 expression on the human endothelial cell line EA.hy 926
European Journal of Immunology, 1993
CD59 (protectin) is an 18-20-kDa inhibitor of the membrane attack complex of complement. It protects homologous cells from complement-mediated damage and has been shown to be present on the endothelial cell membranes both in vitro and in viva In this study we observed that the surface expression of CD59 on the cultured EA.hy 926 endothelial cell line can be up-regulated to an approximately threefold higher level after a 72-h stimulation by the protein kinase C inducers phorbol-12-myristate-13 acetate (PMA; 10 nM) and calcium ionophore, A23187 (100 nM). Similarly, an increase in the level of CD59 expression was seen by the protein kinase A inducer dibutyryl-cyclic adenosine monophosphate. In Northern blot analysis increases were observed in CD59 mRNA expression, particularly in the level of the longest 1.9-kb, 2.1-kb and 5.8-kb transcripts. A functional significance for the increased CD59 expression was implied by an observed increased resistance of the PMA-stimulated EA.hy 926 cells to complement-mediated cell lysis.
CD59 protects rat kidney from complement mediated injury in collaboration with Crry
Kidney International, 2000
CD59 protects rat kidney from complement mediated injury regulatory proteins on the plasma membrane of host in collaboration with Crry. cells. In humans, decay accelerating factor (DAF; CD55) Background. As previously reported, the membrane-bound [1], membrane cofactor protein (MCP, CD46) [2], and complement regulator at the C3 level (Crry/p65) is important CD59 [3-7] are widely distributed in many organs and in maintaining normal integrity of the kidney in rats. However, vessels and play central roles to protect host cells from the role of a complement regulator at the C8/9 level (CD59) is not clear, especially when activation of complement occurs Key words: C3, membrane attack complex, peritubular capillaries, tubulointerstitial injury, renal protective agents.
Proceedings of the National Academy of Sciences of the United States of America, 1992
The gene for CD59 [membrane inhibitor of' reactive lysis (MIRL), protectin], a phosphatidylinositol-linked surface glycoprotein that regulates the formation of the polymeric C9 complex of complement and that is deficient on the abnormal hematopoletic cells of patients with paroxysmal nocturnal hemoglobinuria, consists of four exons saing 20 kilobases. The untransated first exon is preceded by a G+Crich promoter region that lacks a consensus TATA or CAAT motif. The second exon encodes the hydrophobic leader sequence of the protein, and the third exon encodes the aminoterminal portion of the mature protein. The fourth exon encodes the remainder of the mature protein, including the hydrophobic sequence necesry for glycosyl-phosphatidylinositol anchor attachment. The structure ofthe CD59 gene is very simlar to that encoding Ly-6, a murine glycoprotein with which CD59 has some strtural similai. The striking dmilarity in gene stre is further evidence that the two proteins belong to a superfamily of proteins that may also include the uroine activator receptor and a squid glycoprotein of unknown function.