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

人类红细胞上的抗半乳糖 IGG：细胞老化模型

基本信息

批准号：
2049507
负责人：
URI GALILI GALILI
金额：
$ 29.53万
依托单位：
ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 1995-07-31
项目状态：
已结题

项目摘要

The overall objective of this proposal is to further our understanding of the anti-Gal-mediated destruction of human aging red cells and to study the possibility that increased expression of anti-Gal binding sites on human cells may result in the initiation of autoimmune phenomena. Anti-Gal is a natural antibody which we found to constitute 1% of circulating IgG in man, and to interact specifically with Gal alpha1>3Gal beta1>4GlcNac-R epitopes. It is produced in man throughout life as a result of a constant antigenic stimulation by gastrointestinal bacteria expressing similar carbohydrate epitopes. In vivo anti-Gal binds to a de novo exposed epitope on normal senescent red cells and to a similar epitope on large proportion of pathologic red cells in patients with beta-thalassemia and sickle cell disease. A few hundred anti-Gal IgG molecules bound in vivo to red cells in were found to be sufficient for labeling the cells for phagocytosis by macrophages in vitro. This suggested that anti-Gal plays a role in the destruction of aging red cells by interacting with cryptic Gal alpha1.3Ga1 beta1>AGlcNac-R epitopes exposed de novo in the course of normal or pathologic red cell aging. To gain further information on the molecules interacting with anti-Gal, we studied the expression of Gal alpha1>3Ga1 beta1>AG1cNAc-R epitopes on red cells, nucleated cells, and secreted glycoproteins of various mammalian species, and observed a striking evolutionary pattern. The Gal alpha1>3Ga1 beta1>AG1cNAc-R residue was found to be abundant in nonprimate mammals, prosimians, and New World monkeys, but it is undetectable on cells and secreted glycoproteins of Old World monkeys, apes, and human. The absence of this epitope from the latter species was found to result from diminished activity of the enzyme, alpha1>3 galactosyltransferase, which, in the Golg: apparatus, catalyzes the following reaction: Galbeta1>4GlcNAc-R + UDP- Gal>Gal alpha1>3Gal beta1>4GlcNAc-R + UDP. Our studies suggest that the suppression of this enzyme may be the result of an evolutionary event which occurred in the Old World 20-30 million years ago. We have indirect evidence suggesting that the alpha1>3 galactosyltransferase gene has been conserved within the human genome. Our basic current hypothesis is that alpha1>3 galactosyltransferase gene is sparingly expressed in man, resulting in the synthesis of cryptic Gal alpha1>3Ga1 beta1>AG1cNAc epitopes on red cells. Upon aging of the cells, these epitopes are exposed and bind anti-Gal, thus serving as a senescence antigen. Thus a major effort in this project will be to clone the cDNA of alpha1>3 galactosyltransferasde (from a bovine source) and to use it as a probe for studying the presence, expression and mode of regulation of this gene in various human cells including erythropoietic cells. Further, we will test the hypothesis that elevation in alpha1>3 galactosyltransferase activity in human cells, due to deregulation of the gene encoding for this enzyme, may result in autoimmune phenomena mediated by the interaction between anti-Gal and de novo expressed Gal alpha1>3Ga1 beta1>AG1cNAc epitopes. This will be studied particularly in B-lymphocytes from systemic lupus erythematosus patients. When the cDNA probe is obtained, the expression of the alpha 1>3 galactosyltransferase gene will also be studied in a variety of other autoimmune diseases by utilizing the polymerase chain reaction technique. Finally, in continuation of our original proposal, we will study the contribution of the interaction between the anti-Gal antibody and increasingly expressed Gal alpha1>3Ga1 beta1>AG1cNAc epitopes, to the accelerated destruction of red cells in selected hematologic disorders.

这项建议的总目标是进一步增进我们对……的了解