Emerging from a broad interest in the biological functions of the complement system, this proposal focuses on the cytolytic action of human complement from two standpoints: (1) the reciprocal interplay between the C5b-9 membrane attack mechanism and properties of a target membrane influencing susceptibility to lysis; (2) the lysis-inhibiting action of human high density lipoproteins (HDL) and their apoproteins on the terminal events of complement (C) lysis. Within this framework we propose a detailed, quantitative analysis of the interaction of late-acting C components with selected cell types: (a) human erythrocytes from normal donors and patients with paroxysmal nocturnal hemoglobinuria (PNH), as well as normal human red cells chemically modified to produce "PNH-like" lytic sensitivity; (b) guinea pig erythrocytes (also highly vulnerable to human C5b-9); and (c) sheep erythrocytes, for reference. The basis for the differing sensitivity to C lysis of these cell types will be sought by quantitative complement techniques, biophysical probes, chemical analyses, and studies with resealed ghosts and erythrocyte-derived lipid vesicles. The mechanism and precise site of action of the lysis-inhibiting effect of HDL apoproteins will be sought, as will an explanation for their differing effectiveness as inhibitors with the above-listed red cell types. The physiologic significance of this newly recognized function of HDL will be explored with HDL-depleted serum.