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Home , CD59, Platelet, Red blood cell

B l o o d G r o u p R e v i e w CD59: A long-known complement inhibitor has advanced to a group system

C. Weinstock, M. Anliker, and I. von Zabern

The blood group system number 35 is based on CD59, a 20-kDa by Zalman et al.1 from the group of H.J. Muller-Eberhard in La membrane present on a large number of different Jolla, California, and in 1988 by Schönermark et al. from the cells, including erythrocytes. The major function of CD59 is to group of G.M. Hänsch in Heidelberg (Germany).2 This inhibitor protect cells from complement attack. CD59 binds to complement components C8 and C9 and prevents the polymerization of C9, was published under the designations “HRF (homologous which is required for the formation of the membrane attack restriction factor)” and “C8bp (C8 binding ),” complex (MAC). Other functions of CD59 in cellular immunity respectively, to describe its properties.1,2 “C8bp” indicates the are less well defined. CD59 is inserted into the membrane by a glycosylphosphatidylinositol (GPI) anchor. A defect of this anchor binding capacity for C8. The name “HRF” points to a species causes lack of this protein from the membrane, which leads to incompatibility of this “factor” that provides protection from an enhanced sensitivity towards complement attack. Patients with complement attack more effectively in a homologous (e.g., paroxysmal nocturnal (PNH) harbor a varying human erythrocytes as a target of human complement) than in percentage of red clones with a defect in GPI-anchored , including CD59. The most characteristic symptoms of a heterologous system (e.g., human erythrocytes as a target of this disease are episodes of and thromboses. Although guinea pig complement). In 1987, both groups independently CD59 has been classified as a membrane protein for more than described a deficiency of this factor on red blood cells (RBCs) of 25 years, an alloantibody directed against CD59 was found patients with paroxysmal nocturnal hemoglobinuria (PNH).3,4 only recently. So far, the first and sole alloantibody described was detected in a CD59-deficient child. In 2014, CD59 received A similar protein was reported in 1990 by Watts et al. from the status of a blood group system by the International Society B.P. Morgan’s group in Cardiff (UK), which they called “MIP for Red Cell Immunogenetics and Blood (membrane attack complex inhibiting protein).”5 All three of Group Terminology Working Party. Among a variety of almost 20 synonyms, the designation CD59 was chosen for the blood these groups ascribed to this inhibitor a molecular weight of group system and CD59.1 for the wild-type protein. The only approximately 65 kDa, which is significantly higher than that three alleles published to date are null alleles. All CD59-deficient known for CD59 today. This contradiction has never been individuals recognized so far were severely ill, two of whom have resolved; impurities or the formation of protein aggregates are died. Most of the reported cases present with a typical clinical picture within the first year of life that includes neuropathy, possible explanations. , and mild Coombs-negative hemolysis. In one published The first description of an inhibitor with functional case, the application of the complement inhibitor characteristics identical to HRF, C8bp, and MIP, but with a caused a pronounced improvement of the clinical situation. molecular weight of approximately 20 kDa, appeared in 1988 Immunohematology 2015;31:145–151. under the designation “P18.”6 Within 1 year, this protein was Key Words: CD59, HRF20, MIRL, complement regulatory rediscovered by several other groups,7–10 who each named protein, blood group, hemolysis it differently: “MIRL,” for which absence from PNH RBCs was confirmed, “HRF20,” “H19,” and “MEM43.” In 1990, History and Nomenclature Lachmann’s group in Cambridge added another name, “protectin,” to indicate its function in the protection of cells In 2014, the 35th blood group system was allocated from complement attack;11 the CD number 59 was assigned by to CD59, a small membrane glycoprotein of approximately the International Leucocyte Workshop. 20 kDa molecular weight, which is inserted into the Within that same year, the first case of a congenital membrane of all circulating cells and most tissues by a homozygous CD59 deficiency was detected in Japan.12,13 It glycosylphosphatidylinositol (GPI) anchor. An important was not until 2013 that several further publications on CD59- function of this protein is to protect cells from damage by deficient children of North African Jewish or Turkish origin unwanted complement attack. appeared.14–17 Among these cases was a child with a history An inhibitor of the terminal stages of complement with the of transfusions who had formed an directed against functional characteristics of CD59 was first described in 1986 CD59. The identification of this alloantibody allowed CD59

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to be defined as a blood group .16 Finally, in 2014, (Table 3). These introduce premature stop codons, which likely CD59 was accepted by the International Society for Blood prevent the synthesis of functionally active protein. Transfusion (ISBT) Red Cell Immunogenetics and Blood All identified CD59-deficient children were found Group Terminology Working Party as the 35th blood group to carry homozygous alleles, and most were offspring of system (Table 1).18 Although there was a choice among almost consanguineous parents. The expression of CD59 on RBCs of 20 different pre-existing synonyms, the CD classification was heterozygous parents was reported to be lower than normal.14,16 adopted for the designation not only of the antigen but also of the Although the heterozygous patients were apparently without blood group system. The rationale for the uncommon choice of clinical signs, all children with homozygous congenital total a CD number was merely practical: It should be easy to identify deficiency of CD59 suffered from severe disease.12–17 the protein molecule underlying the new blood group system. Furthermore, this decision was made in agreement with the Molecular Basis and Biochemistry Nomenclature Committee of the Complement Society, which suggested the use of the designation CD59 for this complement The CD59 (HGNC: 1689; Gene: 966) was inhibitor. mapped to 11p13, where it spans over 33 kbp.19,20 Alternative splicing of four to seven exons leads Table 1. Blood group system CD59 to multiple transcript variants; eight of them have been Antigen number deposited as reference sequences in the National Center for System 001 Biotechnology Information database. They all differ only in the 035 CD59 CD59.1 5´ untranslated region but encode the same 128– Captured from the Table of Blood Group , version 4.18 preproprotein. The amino-terminal 25–amino acid residues function as signal peptides and are removed during processing The only three alleles published at present are null alleles of the polypeptide. The carboxyl-terminal 26 residues are (Table 2). removed during the attachment of the GPI anchor, leaving a mature CD59 protein, which consists of 77 amino acids.21 Table 2. Alleles encoding the CD59 phenotype null The three-dimensional structure of CD59 has DNA Protein Year of first description been investigated using nuclear magnetic resonance c.123delC p.Val42Serfs*38 199012,13 spectroscopy21,22 and X ray crystallography.23 The core of c.361delG p.Ala121Glnfs c.266G>A p.Cys89Tyr 201214 c.146delA p.Asp49Valfs*31 201315

Genetics and Inheritance

The CD59-deficient individuals encountered to date were of Japanese, North African Jewish, or Turkish origin (Table 3). The amino acid substitution Cys89Tyr is a founder in North African Jews that occurs with a carrier rate of 1 in 66.14 The underlying amino acid substitution involves the loss of a cysteine residue. In the normal protein, Cys89 contributes to a disulfide bond. Lack of this bond may destabilize the tertiary structure of the protein and cause abnormal processing. The authors conclude from their experiments that this missense mutation does not prevent biosynthesis of a CD59-like Fig. 1 Human CD59 consists of (a) a central three-stranded β-sheet molecule. Rather, a failure of the transport to the membrane and (b) an α-helix on one side of the sheet. On the other side is (c) an anti-parallel β-sheet finger carrying the (d) N-. CD59 is or of membrane integration seems to cause the lack of CD59 anchored to the via (e) glycosylphosphatidylinositol. expression.14 The presently known CD59-deficient individuals The star indicates the putative binding site for C8/C9 and intermedilysin. of Japanese and Turkish origin carry frameshift

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Table 3. Clinical presentation of patients with CD59 deficiency

Number of Parents Age of disease Protein Ethnic origin patients Sex consanguineous? onset Clinical presentation References p.Val42Serfs*38, Japanese 1 Male Yes 13 years Symptoms from age 13 to 22 years Yamashina et al.,12 p.Ala121Glnfs • 9 Episodes of PNH-like hemolysis Motoyama et al.13 • No RBC transfusions • 2 Cerebral • No peripheral nervous system involvement reported p.Cys89Tyr North 5 3 Males, 1 Patient 3–7 months • Chronic and paroxysmal Coombs-negative Nevo et al.14 African 2 females hemolysis Jewish • Occasional RBC transfusions • Relapsing peripheral demyelinating disease with polyneuropathy and muscular weakness • Flaccid pareses • Occasional artificial ventilation • Intercurrent • Risk for strokes • 1 Death at age 3.5 years p.Asp49Valfs*31 Turkish 1 Female Yes 7 months • Coombs-negative hemolytic episodes Höchsmann et al.15 • Occasional RBC transfusions • Neurological disease with muscular hypotonia • Flaccid pareses • Temporary mechanical ventilation seizures • Impaired vision • Recurrent Turkish 3 2 Females At least 6–11 months • Strokes Haliloglu et al.17 (sisters), 1 case • Chronic immune-mediated peripheral 1 male neuropathy • Mild chronic Coombs-negative hemolysis • Flaccid paralysis of the lower extremities • Occasional ventilary support • Repeated infections • 1 Death at age 16 years PNH = paroxysmal nocturnal hemoglobinuria; RBC = .

CD59 comprises three β-strands arranged in a central sheet than -derived CD59. The N-linked glycans on (Fig. 1). One side of this central sheet is covered by a short erythrocyte CD59 are very heterogeneous. Over 120 different α-helical structure and the other side by a small two-stranded N-glycans have been isolated from human erythrocyte β-structure that contains the N-terminal end and carries the CD59, and most of them were bi- and tri-antennary neutral . This compact fold of the amino acid chain is and sialylated structures.24 These N-linked stabilized by five disulfide bonds. CD59 shows no homology may account for more than 25 percent of the 20-kDa mass to other complement regulatory proteins. Surprisingly, this of CD59. CD59 has the capability to bind the complement characteristic structure is found in neurotoxins, components C8 and C9. Recombinant CD59 expressed in a mouse leukocyte antigen 6 (Ly-6), and in triplicate in the non-primate cell leading to a different glycosylation pattern -type plasminogen activator receptor, making this a retained both binding activity and species specificity for family of proteins with very heterogeneous members. human C8 and C9.25 This further supports the assumption The carboxy-terminal 12 residues are located between that the carbohydrates do not contribute to its function to the sheets and the cell membrane, connecting the protein bind C8/C9, but are necessary for the three-dimensional at Asn77 to the GPI anchor. No regular secondary structure orientation of the molecule. Ninomiya et al.26 suggested that was found for the carboxy-terminus, which implies the N-linked glycan may dampen the flexibility of CD59 considerable dynamic freedom for the CD59 protein. and may keep the active site in the proper orientation for Nonetheless, a suitable orientation of CD59 is required for interaction with the membrane attack complex (MAC). This binding of C5b-8 complexes. Analyses of protein structure role for the N-glycan of CD59 was suggested by the finding and carbohydrates indicate that CD59 is N-glycosylated at that deglycosylated CD59 lost its ability to prevent , but Asn18.23,24 Glycosylation was found to be cell-type–specific,24 showed no differences in binding to plastic-adsorbed C8 and for example, erythrocyte CD59 molecules carry different C9. In addition, the N-glycan may prevent CD59 molecules

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from aggregation in the cell membrane and protect CD59 and lysis of the cell. To do this, CD59 is equipped with a from .24 binding site for C8α and C9. The putative binding site of CD59 Several potential O-glycosylation sites exist.24 The extent for C8 and C9 was identified in a crevice between the central of O-glycosylation and the role of O-glycans for complement sheet and the helix,21,23 where several hydrophobic residues inhibition are presently not well understood. are located (Fig. 1). It is surprising to consider how “David” overcomes “Goliath”: the small 20-kDa CD59 molecule Physiology and Functional Aspects prevents the 500-kDa C5b-8 complex from interacting with the 66-kDa C9 protein, obviously by occupying a highly CD59 has an important function in protecting cells from specific hydrophobic site.28 unintended damage by activated complement. The task of Fluid-phase forms of CD59, which are devoid of the the is to recognize and remove foreign GPI anchor, occur in urine and other body secretions. Urine materials such as pathogenic as a first line of CD59 has complement inhibitory function but only to an immune defense.27 The system is very complex and consists of approximately 200-fold lower efficiency than erythrocyte more than 35 proteins that act in concert not only to facilitate membrane–bound CD59.29 There are also fluid-phase forms and perforate cells but also to interact in multiple of CD59 that contain the GPI anchor found in seminal plasma ways with the . The defense against infectious and breast milkfat globules.30 agents and also the clearance of “waste” material of the host Despite the action of several complement regulating are functions of the complement system that are indispensable proteins, unwanted damage of host tissues remains a cause for life. However, like all weapons, complement is dangerous for complement-mediated pathological processes in many if it acts uncontrolled. Therefore, the system is well-controlled inflammatory diseases. The aim to design an effective soluble at several stages of activation by regulating proteins. CD59 is recombinant CD59-based therapeutic agent has been the an important inhibitor that is expressed on the membranes subject of several publications.31,32 Drawbacks have been poor of many body cells and stops the assembly of the terminal inhibitory potential under in vivo conditions and the small size lytic MAC. It can, therefore, limit the spread of complement of CD59, which allows rapid clearance in the kidney. In animal activation to nearby (bystander) healthy body cells. models, the use of membrane-targeted CD59 greatly increased Complement can be activated by three pathways. The the in vivo activity of CD59.33 classical pathway is initiated by antigen–antibody complexes The protective effect of CD59 for the host is reversed by or direct binding of its recognition molecule, C1q, to targets. some pathogenic cells and agents. Some tumor cells34 and The alternative pathway is activated on complex carbohydrate enveloped viruses35 arm their surface with CD59 to prevent surfaces and driven by activated forms of C3. The lectin being killed by complement. This is the reason why, for pathway is initiated by lectin-recognition molecules such instance, HIV-1 are resistant to clearance by specific as mannan-binding lectin, , or , which and some cells are resistant to complement- recognize structures present on microorganisms and on mediated cytotoxicity. CD59 not only protects tumor cells cellular debris. At the stage of activated C5 (C5b), the three from being removed by the body’s humoral immune defense activation pathways merge into a final common pathway but also poses a considerable obstacle to that ends with the insertion of the terminal MAC into the immunotherapy. bilayer, causing lysis of the cell. C5b generated by any Streptococcus intermedius uses CD59 as a tool to perforate of these three pathways associates with C6, C7, and C8. C8 the membrane. It secretes the intermedilysin that consists of three non-covalently linked subunits: the α-chain uses CD59 for docking to the membrane and polymerization to (64 kDa) and γ-chain (22 kDa) are disulfide-linked and non- a lytic pore. Intermedilysin binds to the C8/C9 binding site on covalently bound to the ß-chain (64 kDa). The C8α subunit CD59 (Fig. 1) and thereby blocks its MAC inhibiting function.36 anchors C5b-8 to the target cell membrane where the complex Attempts were made to exploit the function of intermedilysin induces the polymerization of 12–18 C9 molecules to a ring- as a CD59 inhibitor. A 114–amino acid recombinant fragment like structure. This “doughnut” generates a membrane pore (rILYd4) was produced that retains the binding site for CD59 that causes leakage, entrance of water, and eventually the but is unable to induce membrane pores.37 Not only does rupture of the cell. rILYd4 have the capacity to block CD59, it also removes CD59 CD59 stops the assembly of the terminal MAC by from the membrane surface, since CD59-rILYd4 complexes are interacting with C8/C9 and thereby prevents pore formation rapidly internalized and degraded. Hence, this recombinant

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protein may have therapeutic potential as an inhibitor in cases Clinical Significance of CD59 and the CD59null where overexpression of CD59 is a danger to the host. It may Phenotype serve as a potential enhancer of complement-mediated lysis of some viruses and tumor cells with upregulated CD59. The importance of CD59 for normal physiological function In addition to its function as a complement inhibitor, can be inferred from the clinical picture of patients carrying alternative roles have been ascribed to CD59 in cellular partial or total defects of CD59. Patients with the acquired immunity. An interaction with the T-cell receptor CD2 was hemolytic disorder PNH harbor a variable proportion of initially postulated but later questioned.38 CD59 seems to RBC clones missing the GPI anchor. The defect is confined contribute to T-cell,39 B-cell, and NK-cell responses, although to hematopoietic cells and acquired by somatic mutations in these roles are much less well understood than its function as the phosphatidylinositol glycan A (PIG-A) gene. On PNH cells, a complement inhibitor.40 Now, because several individuals in addition to CD59, another complement regulatory protein, with CD59 deficiencies are known who suffer not only CD55 (decay accelerating factor, DAF), is missing. PNH is from hemolysis but other severe symptoms, the additional characterized by severe disease with paroxysmal hemolytic physiological roles of CD59 and their relative importance episodes, thromboses, and marrow failure. for the maintenance of normal function may become better Hemolysis in PNH is due to the destruction of PNH cells defined. by complement, because inhibitors are missing to protect the cells. Nevertheless, it is characteristic that no immunoglobulins Antibodies in the System or complement degradation products are found on the patient’s RBCs (“Coombs-negative” hemolytic ). Hemolysis There are 10 cases of congenital total CD59 deficiencies is mainly due to the CD59 defect. Individuals with isolated published to date, and several of these patients have received DAF deficiency (Inab blood group phenotype) do not suffer transfusions. In one child, an anti-CD59 antibody was detected from hemolytic or thrombotic disease, and Inab RBCs are not when the patient was 1.5 years old; the exact immunization more susceptible to complement-mediated lysis than normal event could not be traced back unambiguously, although a RBCs.41 history of transfusions was known.16 The reaction strength Hemolysis is a major cause of illness in patients harboring of anti-CD59 was similar with all test-panel cells using the PNH clones—but the greatest effect on survival is the propensity antiglobulin technique; the reactivity was enhanced after to thromboses, probably resulting from the interaction of papain treatment and abrogated after dithiothreitol treatment complement with and from the defect in GPI-linked of test cells. The antibody titer was maximally 4 (column fibrinolytic and factors. PNH is restricted to technique, antiglobulin test) and declined to RBC clones, whereas the deficiency in CD59 concerns all levels almost undetectable after transfusion therapy was body cells. Patients with a homozygous congenital CD59 discontinued in the course of therapy with the complement deficiency show PNH-like symptoms including hemolysis inhibitor eculizumab. and cerebral . But unlike PNH patients, they suffer Anti-CD59 is considered very rare, and the illness of a from severe central and peripheral polyneuropathy. In Table 3, carrier with typical symptoms of neurological disease and we summarize the presently published cases of patients with atypical PNH may set the investigator on the right track. CD59null phenotype and their symptoms. The Japanese patient CD59 deficiency can be diagnosed by an easy-to-perform differs from the other CD59-deficient children by a later onset column agglutination test commercially available for the of disease (at age 13 years), and no neurological symptoms detection of PNH RBCs.16 RBCs of a CD59-deficient patient have been reported through the age of 22 years. The clinical are not agglutinated by anti-CD59 but react with anti-CD55. picture of the nine children of Turkish or African Jewish origin Flow cytometry and molecular analysis may confirm the was surprisingly similar, with a start of disease within the first diagnosis. year of life, symptoms of a polyneuropathy, “Coombs-negative”

Children of North African Jewish origin with the CD59null paroxysmal hemolytic episodes, and cerebral impairment and allele Cys89Tyr occasionally received RBC transfusions.14 seizures probably due to thromboembolic events. No antibody has been described in these children. This In one case of CD59 deficiency, treatment was started with observation may be correlated to the allele, which seems to eculizumab when the patient was 2.5 years old; eculizumab is allow the synthesis of CD59 but impair the insertion of the an inhibitor of complement at the stage of C5.15 This treatment molecule into the membrane. successfully improved the clinical situation: transfusion

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therapy could be discontinued and the child partially recovered formation of complement transmembrane channels. J Biochem from neurological disease. The positive effect needs to be 1988;104:633–7. confirmed by other patient histories. 7. Holguin MH, Fredrick LR, Bernshaw NJ, Wilcox LA, Parker CJ. Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the Concluding Remarks erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest 1989;84:7–17. 8. Okada N, Harada R, Fujita T, Okada H. A novel membrane Anti-CD59 is an antibody directed against a high- glycoprotein capable of inhibiting membrane attack by prevalence antigen that is not encountered frequently in homologous complement. Int Immunol 1989;1:205–8. routine diagnostics. Presently, only null alleles are known 9. Whitlow MB, Iida K, Stefanova I, Bernard A, Nussenzweig and an anti-CD59 is expected to be found only in rare cases of V. H19, a surface membrane molecule involved in T-cell activation, inhibits channel formation by human complement. CD59 deficiencies. Cell Immunol 1990;126:176–84. Three typical parameters have to be remembered for 10. Stefanova I, Hilgert I, Kristofova H, R, Low MG, Horejsi identification of children affected by a CD59 deficiency: early V. Characterization of a broadly expressed human leucocyte surface antigen MEM-43 anchored in membrane through onset, PNH-like symptoms, and neurological disease. The phosphatidylinositol. Mol Immunol 1989;26:153–61. definition of the new blood group system may help to spread 11. Meri S, Morgan BP, Wing M, et al. Human protectin (CD59), an the knowledge about this disease, and this will benefit CD59- 18-20-kD homologous complement restriction factor, does not deficient patients. Early recognition of the disease allows restrict perforin-mediated lysis. J Exp Med 1990;172:367–70. early intervention and prevention of progression to severe 12. Yamashina M, Ueda E, Kinoshita T, et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor irreversible symptoms. Since the description of six cases (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N in the years 2013 and 2014, at least six new CD59-deficient Engl J Med 1990;323:1184–9. patients have been encountered.17,42 The off-label use of the 13. Motoyama N, Okada N, Yamashina M, Okada H. Paroxysmal nocturnal hemoglobinuria due to hereditary nucleotide deletion complement inhibitor eculizumab is presently a therapeutic in the HRF20 (CD59) gene. Eur J Immunol 1992;22:2669–73. option that needs to be confirmed by additional studies. A 14. Nevo Y, Ben-Zeev B, Tabib A, et al. CD59 deficiency is thorough investigation of CD59-deficient patients may not associated with chronic hemolysis and childhood relapsing only contribute to an improved management of the disease but immune-mediated polyneuropathy. Blood 2013;121:129–35. also to a better definition of the roles of CD59. For instance, 15. Höchsmann B, Dohna-Schwake C, Kyrieleis HA, Pannicke U, Schrezenmeier H. Targeted therapy with eculizumab for the presence of neurological disease in CD59-deficient patients inherited CD59 deficiency. N Engl J Med 2014;370:90–2. points to the importance of MAC for some neurologic disorders 16. Anliker M, von Zabern I, Höchsmann B, et al. A new blood and to a possible therapeutic effect of complement inhibition. group antigen is defined by anti-CD59, detected in a CD59- deficient patient. Transfusion 2014;54:1817–22. 17. Haliloglu G, Maluenda J, Sayinbatur B, et al. Early-onset References chronic axonal neuropathy, strokes, and hemolysis: inherited CD59 deficiency. Neurology 2015;84:1220–4. 1. Zalman LS, Wood LM, Muller-Eberhard HJ. Isolation of a human erythrocyte membrane protein capable of inhibiting 18. International Society of Blood Transfusion. Table of blood expression of homologous complement transmembrane group antigens v4.0 141224 ISBT Working Party Red Cell channels. Proc Natl Acad Sci U S A 1986;83:6975–9. Immunogenetics and Blood Group Terminology. http://www. isbtweb.org/working-parties/red-cell-immunogenetics-and- 2. Schönermark S, Filsinger S, Berger B, et al. The C8-binding blood-group-terminology/. protein of human erythrocytes: interaction with the components of the complement-attack phase. 19. Tone M, Walsh LA, Waldmann H. Gene structure of human 1988;63:585–90. CD59 and demonstration that discrete mRNAs are generated by alternative polyadenylation. J Mol Biol 1992;227:971–6. 3. Zalman LS, Wood LM, Frank MM, Muller-Eberhard HJ. Deficiency of the homologous restriction factor in paroxysmal 20. Holguin MH, Martin CB, Eggett T, Parker CJ. Analysis of nocturnal hemoglobinuria. J Exp Med 1987;165:572–7. the gene that encodes the complement regulatory protein, membrane inhibitor of reactive lysis (CD59): identification 4. Hänsch GM, Schönermark S, Roelcke D. Paroxysmal nocturnal of an alternatively spliced exon and characterization of the hemoglobinuria type III: lack of an erythrocyte membrane transcriptional regulatory regions of the promoter. J Immunol protein restricting the lysis by C5b-9. J Clin Invest 1987;80: 1996;157:1659–68. 7–12. 21. Fletcher CM, Harrison RA, Lachmann PJ, Neuhaus D. 5. Watts MJ, Dankert JR, Morgan EP. Isolation and Structure of a soluble, glycosylated form of the human characterization of a membrane-attack-complex-inhibiting complement regulatory protein CD59. Structure 1994;2: protein present in human and other biological fluids. 185–99. Biochem J 1990;265:471–7. 22. Kieffer B, Driscoll PC, Campbell ID, Willis AC, van der Merwe 6. Sugita Y, Nakano Y, Tomita M. Isolation from human PA, Davis SJ. 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extracellular region of the complement regulatory protein 34. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. CD59, a new cell-surface protein domain related to snake Obstacles to cancer immunotherapy: expression of membrane venom neurotoxins. Biochemistry 1994;33:4471–82. complement regulatory proteins (mCRPs) in tumors. Mol 23. Huang Y, Fedarovich A, Tomlinson S, Davies C. Crystal Immunol 2003;40:109–23. structure of CD59: implications for molecular recognition of 35. Hu W, Yu Q, Hu N, et al. A high-affinity inhibitor of human the complement proteins C8 and C9 in the membrane-attack CD59 enhances complement-mediated virolysis of HIV-1: complex. Acta Crystallogr D Biol Crystallogr 2007;63:714–21. implications for treatment of HIV-1/AIDS. J Immunol 2010; 24. Rudd PM, Morgan BP, Wormald MR, et al. The glycosylation of 184:359–68. the complement regulatory protein, human erythrocyte CD59. 36. Wickham SE, Hotze EM, Farrand AJ, et al. Mapping the J Biol Chem 1997;272:7229–44. intermedilysin-human CD59 receptor interface reveals a 25. Zhao J, Rollins SA, Maher SE, Bothwell AL, Sims PJ. Amplified deep correspondence with the binding site on CD59 for in CD59-transfected Chinese hamster ovary complement binding proteins C8alpha and C9. J Biol Chem cells confers protection against the membrane attack complex 2011;286:20952–62. of human complement. J Biol Chem 1991;266:13418–22. 37. Cai B, Xie S, Liu F, et al. Rapid degradation of the complement 26. Ninomiya H, Stewart BH, Rollins SA, Zhao J, Bothwell regulator, CD59, by a novel inhibitor. J Biol Chem 2014;289: AL, Sims PJ. Contribution of the N-linked carbohydrate 12109–25. of erythrocyte antigen CD59 to its complement-inhibitory 38. van der Merwe PA, Barclay AN, Mason DW, et al. Human cell- activity. J Biol Chem 1992;267:8404–10. adhesion molecule CD2 binds CD58 (LFA-3) with a very low 27. Carroll MV, Sim RB. Complement in health and disease. Adv affinity and an extremely fast dissociation rate but does not Deliv Rev 2011;63:965–75. bind CD48 or CD59. Biochemistry 1994;33:10149–60. 28. Aleshin AE, Schraufstatter IU, Stec B, Bankston LA, Liddington 39. Baalasubramanian S, Harris CL, Donev RM, et al. CD59a is RC, DiScipio RG. Structure of complement C6 suggests a the primary regulator of membrane attack complex assembly mechanism for initiation and unidirectional, sequential in the mouse. J Immunol 2004;173:3684–92. assembly of membrane attack complex (MAC). J Biol Chem 40. Kimberley FC, Sivasankar B, Paul MB. Alternative roles for 2012;287:10210–22. CD59. Mol Immunol 2007;44:73–81. 29. Meri S, Lehto T, Sutton CW, Tyynela J, Baumann M. Structural 41. Yazer MH, Judd WJ, Davenport RD, et al. Case report composition and functional characterization of soluble CD59: and literature review: transient Inab phenotype and an heterogeneity of the oligosaccharide and glycophosphoinositol agglutinating anti-IFC in a patient with a gastrointestinal (GPI) anchor revealed by laser-desorption mass spectrometric problem. Transfusion 2006;46:1537–42. analysis. Biochem J 1996;316:923–35. 42. Höchsmann B. Personal communication. 2015. 30. Hakulinen J, Meri S. Shedding and enrichment of the -anchored complement lysis inhibitor protectin (CD59) into milk globules. Immunology 1995;85:495–501. Christof Weinstock, MD (corresponding author), Institute for Clinical 31. Huang Y, Smith CA, Song H, Morgan BP, Abagyan R, and Immunogenetics, German Red Cross Tomlinson S. Insights into the human CD59 complement Blood Service Baden-Württemberg–Hessen, and University of Ulm, binding interface toward engineering new therapeutics. J Biol Germany, Helmholtzstr. 10, 89081 Ulm, Germany, c.weinstock@ Chem 2005;280:34073–9. blutspende.de; Markus Anliker, MD, Institute for Clinical Transfusion 32. Leath KJ, Johnson S, Roversi P, et al. High-resolution structures Medicine and Immunogenetics, German Red Cross Blood Service of bacterially expressed soluble human CD59. Acta Crystallogr Baden-Württemberg–Hessen, and University of Ulm, Germany; Sect F Struct Biol Cryst Commun 2007;63:648–52. and Inge von Zabern, MD, PhD, Institute for Clinical Transfusion 33. Fraser DA, Harris CL, Williams AS, et al. Generation of a Medicine and Immunogenetics, German Red Cross Blood Service recombinant, membrane-targeted form of the complement Baden-Württemberg–Hessen, and University of Ulm, Germany. regulator CD59: activity in vitro and in vivo. J Biol Chem 2003; 278:4 8921–7.

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