Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting

• DOI: 10.1073/pnas.96.2.628
• Publication Date: 2002-07-26T14:42:40Z
• Authors: Xiujun Sun; Colin D. Funk; Chengjun Deng; Arvind Sahu; John D. Lambris; Wen-Chao Song
• Keywords: Decay-accelerating factor; Heterologous; Lectin pathway; Paroxysmal nocturnal hemoglobinuria; Complement factor B; Zymosan; CD59

Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that inhibits both the classical and alternative pathways of complement activation. DAF has been studied extensively in humans under two clinical settings: when absent from erythrocytes paroxysmal nocturnal hemoglobinuria (PNH) patients, who suffer complement-mediated hemolytic anemia, transgenic pigs expressing human DAF, which have developed to help overcome hyperacute rejection xenotransplantation. Nevertheless, exact role regulating activation vivo on cell surface species specificity this molecule remain be fully characterized. To address these issues, we used gene targeting produce mice lacking GPI-anchored DAF. We found deficient showed no increase spontaneous but exhibited impaired regulation zymosan-initiated bystander antibody-triggered pathway vitro, resulting enhanced deposition. Despite high level C3 fixation, homologous hemolysis occurred. It noteworthy GPI-linked knockout erythrocytes, tested with guinea pig sera, were more susceptible heterologous lysis than normal erythrocytes. These results suggest capable as well via or pathway. They also indicate deficiency alone not sufficient cause hemolysis. In contrast, assembly membrane-attack complex properly regulated, case PNH erythrocyte activity deposition could lead increased reaction.