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

The glycolipid-anchored glycoprotein CD59 inhibits assembly of the lytic me mbrane attack complex of complement by incorporation into the forming compl ex. Absence of CD59 and other glycolipid-anchored molecules on circulating cells in the human hemolytic disorder paroxysmal nocturnal hemoglobinuria i s associated with intravascular hemolysis and thrombosis. To examine the ro le 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 a ntibody. Despite the complete absence of CD59, mice were healthy and fertil e. Erythrocytes in vitro displayed increased susceptibility to complement a nd were positive in an acidified serum lysis test. Despite this, CD59(-/-) mice were not anemic but had elevated reticulocyte counts, indicating accel erated erythrocyte turnover. Fresh plasma and urine from CD59(-/-) mice con tained increased amounts of hemoglobin when compared with littermate contro ls, providing further evidence for spontaneous intravascular hemolysis. Int ravascular 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 fr om membrane attack complex damage in health and during diseases in which co mplement Is activated. (C) 2001 by The American Society of Hematology.