Although complement plays an essential role in host defense, activated complement is a double-edged sword that has the potential to inflict substantial damages to self-tissues. One way by which host tissues avoid complement mediated autologous attack is to express specific complement inhibiting proteins on their cell surface. Decay accelerating factor (DAF, C:D55) is a glycosylphosphatidylinositol (GPI)-anchored membrane regulator that inhibits both the classical and alternative pathways of complement activation. Deficiency of DAF on human erythrocytes contributes to the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by heightened sensitivity of affected erythrocytes to complement-mediated lysis. Human DAF has also been experimented on as a potential therapeutic agent to prevent hyperacute rejection in xenotransplantation. To evaluate the protective role of DAF in pathological processes where complement activation might occur, the investigators have generated DAF knockout (KO) mice by gene targeting. In this study, they propose to use these mice to evaluate the involvement of complement and its regulation by DAF in two models of autoantibody-mediated tissue damage: autoimmune hemolytic anemia and anti-GBM glomerulonephritis. Their central hypothesis is that membrane complement regulating proteins such as DAF represent an important factor in determining whether and to what degree the complement system is involved in autoimmune tissue damage.
The specific aims are: 1) to determine if DAF offers a protective role in complement-mediated immune hemolytic anemia. They will assess the role of complement in anti-erythrocyte IgM- and IgG-induced murine immune hemolytic anemia and determine whether DAF-deficiency exacerbates the disease. DAF-, (23- and FcR-KO and DAF/FcR double KO mice will be used to dissect the roles of complement FcR and DAF in the destruction of autoantibody-coated erythrocytes. 2) to determine if DAF offers a protective role in anti-glomerular basement membrane (GBM)-induced murine glomerulonephritis. By using DAF KO and DAI /FcR, DAF/C3 double KO mice, we will determine if anti-GBM-induced glomerular injury is exacerbated in the DAF KO mice and whether increased early (C3a, C5a) or late (C5b-9) complement activity is responsible. These studies will not only establish a physiological role of DAF in autoimmune reactions but also will shed light on the debate concerning the role of complement in autoimmune diseases.
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