Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria

• Published in: Blood Vol. 98; no. 2; pp. 442 - 449
• Main Authors: Holt, Dewi S., Botto, Marina, Bygrave, Anne E., Hanna, S. Melanie, Walport, Mark J., Morgan, B. Paul
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.07.2001; The Americain Society of Hematology
• Subjects: Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Blood Platelets - chemistry; CD59 Antigens - genetics; CD59 Antigens - physiology; Complement Activation; Diseases of red blood cells; Elapid Venoms - pharmacology; Erythrocytes - chemistry; Female; Flow Cytometry; Gene Deletion; Hematologic and hematopoietic diseases; Hemoglobinuria - genetics; Hemolysis - genetics; Heterozygote; Homozygote; Leukocytes - chemistry; Male; Medical sciences; Mice; Mice, Knockout; Reticulocyte Count; Sex Characteristics; Hemolysis; Transmembrane protein; Animal model; Erythrocytic membrane disease; Pathogenesis; Rodentia; Glycoprotein; Red blood cell; Hemopathy; Complement; Vertebrata; Mammalia; Nocturnal paroxystic anemia; Gene; Mouse; Animal; Plasma membrane; Deletion; Membrane attack complex
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V98.2.442

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 hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation. CD59−/− mice will provide a tool for characterizing the importance of CD59 in protection of self tissues from membrane attack complex damage in health and during diseases in which complement is activated.