1560 Prevention of Complement Activation on Cells

A key step in complement activation on targets is the deposition of C4b and/ or C3b fragments. These major cleavage products of C3 and C4 can associate covalently with the target surface (reviewed in 1) and then serve as anchors for the assembly of C3 and C5 convertases, the amplifying enzymes of the cascade. This amplification must be focused only on the target and must not occur on host cells. Moreover, in the course of this focused amplification, large numbers of nascent C4b and C3b fragments are liberated into the fluid phase. Most react with water, but some by chance could bind to nearby host cells and lead to their damage. For this and possibly other reasons, the activities of bound, as well as free, C3b and C4b fragments are under strict control by a complex system of serum and membrane proteins. Recent evidence (2, 3) suggests that regulation of the activities of substratebound C4b and C3b is distinct from control of the fluid phase fragments. The functions of the former are controlled mainly by two membrane proteins: the C3b/C4b receptor (CR1) 1 and the decay-accelerating factor (DAF). CR1 dissociates C2 and factor B from C4b and C3b in C3 and C5 convertase complexes (2-5) and promotes the cleavage of C3b (2, 4, 6, 7) and C4b (3, 5) by the serum enzyme C3b/C4b inactivator (I). DAF has been shown also to enhance the decay dissociation of C2 and factor B from C3 convertases (8, 9). The reason for the apparent redundancy in regulatory activities of the two membrane factors and their respective roles in convertase control has remained unclear. Abnormalities of CR1 have been found in systemic lupus erythematosus (SLE) (10-13), a condition associated with defective immune complex handling, and abnormalities of DAF have been found in paroxysmal nocturnal hemoglobinuria (PNH) (9, 14, 15), a condition associated with heightened susceptibility of blood, cells to lysis. In the present paper we purified DAF to homogeneity from the stroma of