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.
| Kinoshita, T; Rosenfeld, S I; Nussenzweig, V (1987) A high m.w. form of decay-accelerating factor (DAF-2) exhibits size abnormalities in paroxysmal nocturnal hemoglobinuria erythrocytes. J Immunol 138:2994-8 |
| Rosenfeld, S I; Jenkins Jr, D E; Leddy, J P (1986) Enhanced reactive lysis of paroxysmal nocturnal hemoglobinuria erythrocytes. Studies on C9 binding and incorporation into high molecular weight complexes. J Exp Med 164:981-97 |
| Rosenfeld, S I; Jenkins Jr, D E; Leddy, J P (1985) Enhanced reactive lysis of paroxysmal nocturnal hemoglobinuria erythrocytes by C5b-9 does not involve increased C7 binding or cell-bound C3b. J Immunol 134:506-11 |
