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

目的是研究一种新描述的自然人的作用 抗α(1-3)-半乳糖基免疫球蛋白抗体(抗-Gal) 选择性地破坏人体衰老的红细胞。值得注意的是，这 抗体占所有循环免疫球蛋白的1%。正常情况下 在个体中，它被发现在体内只与小分子结合 高密度衰老的红细胞亚群而不是年轻的 细胞。此外，它与更大比例的各种病理组织结合在一起 似乎正在经历加速衰老的红细胞。的约束性 红细胞的抗半乳糖胺使其对吞噬功能敏感。我们假设 一种含有α-半乳糖残基的隐蔽抗原 当红细胞变得更致密时，结合抗半乳糖的物质暴露在红细胞上 在血液循环和某些病理状态下衰老的同时， 加速老化的红细胞可能会导致过早接触 抗半乳糖结合部位。我们已经证明GalAlpha(1到3)Gal表位 结合抗Gal的抗体在非灵长类哺乳动物和新大陆中大量存在 猴子和东半球猴子的红细胞中几乎检测不到 天哪。我们认为这种抗原的表达已经 进化地被压制成一种神秘的形式，伴随着 生产高滴度的抗Gal抗体。 为了检验这些假设，我们将探索这种神秘的本质 通过生物化学研究人红细胞膜分子的抗原 与反Gal病毒相互作用。反Gal的空间排列 还将分析与其他膜相关的结合位置 抗原，通过使用胶体金标记的抗体和凝集素 免疫电子显微镜。此外，为了研究这一机制 抗Gal结合部位暴露，体内各种过程可能 衰老过程中的诱导暴露将通过体外实验进行研究 意思是。这将包括巨噬细胞对红色的蛋白分解作用。 细胞和对红细胞的氧化损伤。此外，可能的 这一衰老过程在其他灵长类动物中的发生将使用 以黑猩猩为模型，研究黑猩猩与黑猩猩之间的系统发育关系 天然抗半乳糖胺及其结合部位将在各种其他 灵长类和哺乳动物。最后，我们将开发一种灵敏的检测方法 在溶血状态的红细胞上存在这种抗体，以努力 检验生理衰老加速可能起到作用的假设 通过这种抗体缩短了红细胞的寿命。这个 抗Gal与其隐蔽抗原相互作用的测定 应该用来确定它在红细胞生理和病理中的作用 老化过程。鉴于观察到的抗Gal与 人脑组织匀浆，这项研究可能提供新的见解 免疫系统在其他组织衰老过程中的作用 井。

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.