The objective is to study the role of a newly-described natural human antibody, anti-Alpha(1 to 3)-galactosyl IgG (anti-Gal), in mediating the selective destruction of senescent red cells in man. Remarkably, this antibody constitutes up to 1% of all circulating IgG. In normal individuals, it has been found to bind in vivo only to the small subpopulation of high density senescent red cells and not to younger cells. Furthermore, it binds to larger proportions of various pathologic red cells which appear to undergo accelerated senescence. The binding of the anti-Gal to red cells sensitizes them for phagocytosis. We hypothesize that a cryptic antigen bearing Alpha-galactosyl residues and capable of binding the anti-Gal is exposed on red cells when they become more dense while aging in the circulation and that in some pathologic states, accelerated aging of red cells may result in premature exposure of the anti-Gal binding site. We have shown that GalAlpha(1 to 3)Gal epitopes binding the anti-Gal are abundant in non-primate mammals and in New World monkeys and virtually undetectable in red cells of Old World monkeys and man. We suggest that the expression of this antigen has been evolutionarily suppressed into a cryptic form, concomitant with the production of high titers of anti-Gal. To test these hypotheses, we will explore the nature of this cryptic antigen by biochemically studying the membrane molecules in human red cells which interact with anti-Gal. The spatial arrangement of the anti-Gal binding site will also be analyzed in relation to the other membrane antigens, by employing colloidal gold-labeled antibodies and lectins in immunoelectron microscopy. Further, to study the mechanism by which the anti-Gal binding site is exposed, various in vivo processes which may induce exposure in the course of senescence will be studied by in vitro means. These will include the proteolytic effect of macrophages on red cells and oxidative damage to red cells. In addition, the possible occurrence of this aging process in other primates will be studied using chimpanzees as a model, and the phylogenetic relationship between the natural anti-Gal and its binding site will be analyzed in various other primates and mammals. Finally, we will develop a sensitive assay for the presence of this antibody on red cells in hemolytic states in an effort to test the hypothesis that accelerated physiologic senescence may contribute to the shortened life span of red cells via this antibody. The determination of the interaction of the anti-Gal and its cryptic antigen should serve to define its role in red cell physiologic and pathologic aging process. In view of the observed interaction of the anti-Gal with human brain tissue homogenate, this study may provide new insights into the contribution of the immune system to the aging process of other tissues as well.
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