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Activation of the Alternative Complement Pathway by Exposure of Phosphatidylethanolamine and Phosphatidylserine on Erythrocytes from Sickle Cell Disease Patients

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Activation of the Alternative Complement Pathway by Exposure of Phosphatidylethanolamine and Phosphatidylserine on Erythrocytes from Sickle Cell Disease Patients Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. R H Wang, … , M E Medof, C Mold J Clin Invest. 1993;92(3):1326-1335. https://doi.org/10.1172/JCI116706. Research Article Deoxygenation of erythrocytes from sickle cell anemia (SCA) patients alters membrane phospholipid distribution with increased exposure of phosphatidylethanolamine (PE) and phosphatidylserine (PS) on the outer leaflet. This study investigated whether altered membrane phospholipid exposure on sickle erythrocytes results in complement activation. In vitro deoxygenation of sickle but not normal erythrocytes resulted in complement activation measured by C3 binding. Additional evidence indicated that this activation was the result of the alterations in membrane phospholipids. First, complement was activated by normal erythrocytes after incubation with sodium tetrathionate, which produces similar phospholipid changes. Second, antibody was not required for complement activation by sickle or tetrathionate-treated erythrocytes. Third, the membrane regulatory proteins, decay-accelerating factor (CD55) and the C3b/C4b receptor (CD35), were normal on sickle and tetrathionate-treated erythrocytes. Finally, insertion of PE or PS into normal erythrocytes induced alternative pathway activation. SCA patients in crisis exhibited increased plasma factor Bb levels compared with baseline, and erythrocytes isolated from hospitalized SCA patients had increased levels of bound C3, indicating that alternative pathway activation occurs in vivo. Activation of complement may be a contributing factor in sickle crisis episodes, shortening the life span of erythrocytes and decreasing host defense against infections. Find the latest version: https://jci.me/116706/pdf Activation of the Alternative Complement Pathway by Exposure of Phosphatidylethanolamine and Phosphatidylserine on Erythrocytes from Sickle Cell Disease Patients Robert H. Wang,* George Phillips, Jr.,$ M. Edward Medof, and Carolyn Mold *Department ofMicrobiology, University ofNew Mexico, Albuquerque, New Mexico 87131; tDepartment ofMedicine, Duke University School ofMedicine, Durham, North Carolina 27710; andlInstitute ofPathology, Case Western Reserve University, Cleveland, Ohio 44106 Abstract become deformed into a sickle shape as a result of polymeriza- tion of Hb S within the cell. Sickle erythrocytes have a shorter Deoxygenation of erythrocytes from sickle cell anemia (SCA) life span than normal erythrocytes and are less elastic, more patients alters membrane phospholipid distribution with in- easily trapped in capillaries, and more prone to physiological creased exposure of phosphatidylethanolamine (PE) and phos- insults ( 1, 2). Sickle erythrocytes also have altered membrane phatidylserine (PS) on the outer leaflet. This study investi- phospholipid distribution after deoxygenation (3-5). gated whether altered membrane phospholipid exposure on Phospholipids on normal human erythrocytes are asymmet- sickle erythrocytes results in complement activation. In vitro rically distributed across the bilayers of the cell membrane (5, deoxygenation of sickle but not normal erythrocytes resulted in 6). Phosphatidylcholine (PC), sphingomyelin, and < 10% of complement activation measured by C3 binding. Additional evi- the total phosphatidylethanolamine (PE) are located in the ex- dence indicated that this activation was the result of the alter- ternal leaflet. Most of the PE and all of the phosphatidylserine ations in membrane phospholipids. First, complement was acti- (PS) are located on the inner leaflet of the membrane bilayer. vated by normal erythrocytes after incubation with sodium tet- Deoxygenation of Hb SS erythrocytes results in increased ex- rathionate, which produces similar phospholipid changes. posure of PE and PS on the outer leaflet (3-5). The abnormal Second, antibody was not required for complement activation exposure of PS on sickle erythrocytes has been related to in- by sickle or tetrathionate-treated erythrocytes. Third, the creased adherence to endothelial cells (2), procoagulant activ- membrane regulatory proteins, decay-accelerating factor ity (7), and adherence to mononuclear phagocytic cells (8, 9). (CD55) and the C3b/C4b receptor (CD35), were normal on Patients with SCA are susceptible to recurrent bacterial in- sickle and tetrathionate-treated erythrocytes. Finally, insertion fections, particularly with Streptococcus pneumoniae (10). of PE or PS into normal erythrocytes induced alternative path- The higher propensity for bacterial infections has been attrib- way activation. SCA patients in crisis exhibited increased uted to decreased splenic function (11). Abnormal opsonic plasma factor Bb levels compared with baseline, and erythro- activity ( 12-14) and evidence of alternative complement path- cytes isolated from hospitalized SCA patients had increased way activation ( 15-18) have been observed in serum from pa- levels of bound C3, indicating that alternative pathway activa- tients with SCA, suggesting that decreased serum complement tion occurs in vivo. Activation of complement may be a contrib- may also contribute to the higher risk of bacterial infections. uting factor in sickle crisis episodes, shortening the life span of The source of this complement activation has not been deter- erythrocytes, and decreasing host defense against infections. mined. (J. Clin. Invest. 1993. 92:1326-1335.) Key words: phospho- The alternative complement pathway is a primary host de- lipid * membrane * C3 * factor B fense mechanism, which can be activated by bacterial polysac- charides, virus-infected cells, and other substances in the ab- Introduction sence of specific antibodies ( 19, 20). Upon activation, C3b molecules are deposited covalently on the activator surface leading to opsonization and formation of the lytic membrane Sickle cell anemia (SCA)' is a genetic disease resulting from a attack complex. Liposomes containing PE (21) and/or PS single amino acid change in the ,3-globin subunit of hemoglo- (22-24) activate the alternative complement pathway in hu- bin (1). This abnormal hemoglobin is termed hemoglobin S man serum. C3b deposition on normal host cells is inhibited by (Hb S), and homozygous individuals (Hb SS) develop a membrane regulatory proteins, including decay-accelerating chronic hemolytic anemia, chronic and progressive tissue and organ damage, and acute painful vasoocclusive crises. Erythro- cytes from SCA patients when exposed to low oxygen pressure 1. Abbreviations used in this paper: CR1, C3b/C4b receptor; DAF, decay-accelerating factor; DPPC, dipalmitoyl-phosphatidylcholine; DPPE, dipalmitoyl-phosphatidylethanolamine; DPPS, dipalmitoyl- Address correspondence and reprint requests to Dr. Carolyn Mold, phosphatidylserine; GVB, Veronal buffer containing 0.1% gelatin; Hb Department of Microbiology, University of New Mexico School of S, hemoglobin S; Hb SS, hemoglobin S of homozygous individuals; Medicine, Albuquerque, NM 87131. MC540, merocyanine 540; MCP, membrane cofactor protein; Receivedfor publication 12 October 1992 and in revisedform 22 NBD-PC, 1-acyl-2[6- [(7-nitro-2- 1,3-benzoxadiazol-4-yl)amino] April 1993. caproyl]-sn-glycerol-3-phosphocholine; NBD-PE, I-acyl-2- [6-[7- nitro-2-1,3-benzoxadiazol-4-yl)amino]caproyl]-sn-glycerol-3- phos- J. Clin. Invest. phoethanolamine; NBD-PS, I-palmitoyl-2-[6-[7-nitro-2-1,3-benzox- © The American Society for Clinical Investigation, Inc. yadiazol-4-yl) amino ] caproyl ] -sn-glycerol-3-phosphoserine; PC, 0021-9738/93/09/1326/10 $2.00 phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphati- Volume 92, September 1993, 1326-1335 dylserine; SCA, sickle cell anemia; VBS, Veronal buffer. 1326 R. H. Wang, G. Phillips, M. E. MedofJ and C. Mold factor (DAF, CD55) (25), membrane cofactor protein (MCP, trations in GVB as previously described (38). Human erythrocytes at CD46) (25), and the C3b/C4b receptor (CR1, CD35) (26). I09 cells/ml in VBS were incubated with an equal volume ofthe puri- DAF, MCP, and CR1 efficiently modulate complement activa- fied component mixture for 30 min at 370C. After incubation, erythro- tion by both the classical and alternative pathways by prevent- cytes were washed, lysed, and frozen before testing C3 deposition. convertases on autologous cells C3 binding assays. A competitive ELISA using horseradish peroxi- ing the formation ofC3 and C5 dase-conjugated anti-C3 antibody (Cappel Laboratories, Durham, and promoting the breakdown of bound C4b and C3b (27- NC) was used to quantitate C3 deposition on erythrocytes as previ- 31 ). Of these, only DAF and CR1 are found on erythrocytes. ously described (21). The amount of C3 bound to erythrocytes was The present work has tested the hypothesis that membrane calculated from a standard curve prepared using 0.03-8 jg/ ml purified phospholipid changes in deoxygenated sickle erythrocytes lead C3. Values from EDTA controls were subtracted. The assay detects to complement activation through the alternative pathway. C3d as well as intact C3, C3b, and iC3b. The molecular weight of C3b The results indicate that deoxygenated sickle erythrocytes acti- was used to calculate molecules bound per cell. For experiments to vate the alternative complement pathway in autologous serum assess the presence of C3 fragments on washed erythrocytes without and that similar activation can be induced by several other serum incubation, washed erythrocytes were lysed at a concentration of treatments that
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