ANTI-GAL IGG ON HUMAN RED CELLS--A MODEL FOR CELL AGING

目的是研究一个新描述的自然人的作用 抗体，抗-α（1至3）-半乳糖基IgG（抗-Gal），在介导 选择性破坏人体衰老的红细胞。值得注意的是， 抗体占所有循环IgG的1%。 正常 个体，它已被发现在体内仅结合到小的 高密度衰老红细胞亚群和不年轻 细胞 此外，它与各种病理性的 红细胞似乎正在加速衰老。 的结合 红细胞的抗Gal使它们对吞噬作用敏感。 我们假设 携带α-半乳糖残基并能够 当红细胞变得更密集时， 在循环中老化和某些病理状态下， 红细胞的加速老化可能导致 抗Gal结合位点。 我们已经表明GalAlpha（1至3）Gal表位 在非灵长类哺乳动物和新世界中， 在旧大陆猴的红细胞中几乎检测不到， 伙计 我们认为，这种抗原的表达已被 进化上被压制成一种神秘的形式，伴随着 产生高滴度的抗Gal。 为了验证这些假设，我们将探索这种神秘的性质。 通过对人红细胞膜分子的生物化学研究 与抗半乳糖抗体相互作用 抗Gal的空间排列 结合位点也将相对于另一个膜进行分析 抗原，通过采用胶体金标记的抗体和凝集素， 免疫电镜 此外，为了研究 抗Gal结合位点暴露，各种体内过程， 在衰老过程中的诱导暴露将通过体外研究 手段 这些将包括巨噬细胞对红细胞的蛋白水解作用。 细胞和红细胞的氧化损伤。 此外，可能的 其他灵长类动物中这种衰老过程的发生将使用 黑猩猩作为一个模型，和系统发育之间的关系， 天然抗Gal及其结合位点将在各种其他 灵长类动物和哺乳动物。 最后，我们将开发一种灵敏的检测方法， 这种抗体在溶血状态的红细胞上的存在， 测试加速生理衰老可能有助于 红细胞寿命的缩短。 的 抗Gal抗体与其隐蔽抗原相互作用的测定 应有助于确定其在红细胞生理和病理中作用 老化过程 鉴于所观察到的抗Gal与 人脑组织匀浆，这项研究可能会提供新的见解， 免疫系统对其他组织衰老过程的贡献， 好.

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.