The destruction of red cells by antibodies in man. I. Observations of the sequestration and lysis of red cells altered by immune mechanisms.

Much of our present knowledge of the pathologic physiology of the acquired hemolytic anemias originated from observations of the fate of heterologous red cells in immunized animals and of the syndromes produced in animals by injections of heterologous anti-red cell sera (1-17). The frank hemolysins present in anti-red cell sera seemed to provide a complete explanation for the experimental findings, but it was early stressed by Muir and M'Nee (6) and by Banti (8) that the hemolytic action of hemolysin-containing sera was greater in extent and slower in evolution when injected into the intact animal than when added to red cells in vitro. It was also pointed out by Banti (8) and by others (12, 14) that anti-red cell sera produced spherocytosis of red cells in vivo but failed to do so in vitro. In humans it was proposed that spontaneous hemolysins may provoke the clinical picture of acquired hemolytic anemia (5, 9, 10), particularly when associated with high titers of cold agglutinins (18, 19). However, clinical experience with acquired hemolytic anemia as well as with blood transfusion reactions and erythroblastosis fetalis has indicated that these hemolytic syndromes are generally not associated with hemolysins demonstrable in vitro (20, 21); and the injection into animals (14, 17, 22) or into man (23-26) of antibodies which agglutinate but do not directly hemolyze red cells in vitro may reproduce the full picture of clinical hemolytic disease. Indeed, a number of investigators have observed the formation of intravascular red cell agglutinates in vivo after injection of heterologous or homologous immune serum (4, 14, 15, 24, 27). In many patients suffering from hemolytic reactions, in almost all infants afflicted with erythroI This investigation was supported in part by a grant from the Helen Hay Whitney Foundation, and by Research Grants RG3507(C3) and H1227 from the National Institutes of Health, Public Health Service. blastosis fetalis, and in most patients with acquired hemolytic anemia, it is not even possible to demonstrate "complete" agglutinins. In these conditions the antibodies (actual or presumed) are agglutinins only in the sense that they "sensitize" red cells to the agglutinating effect in vitro of antiglobulin (Coombs) serum, of sufficient concentrations of plasma proteins or of certain other large anisometric anionic molecules (28-30). Although the hemolytic effect of hemolysins in vivo may be inferred from their manifest effects in vitro, the mechanism of the hemolytic action in vivo of agglutinating and of sensitizing antibodies has remained obscure. In the present study, use was made of the Cr' method for labelling small volumes of red cells for red cell survival studies (31, 32) and for determining the sites of red cell sequestration in living subjects (33). The subjects on whom observations were made included normal adults who had previously suffered accidental isoimmunization through transfusion or pregnancy. Some of these findings have been presented in preliminary form elsewhere (34-36).