IMMUNE SENESCENCE AUTOIMMUNITY AND AGING

免疫衰老 自身免疫与衰老

• 批准号: 3078719
• 负责人: DANIEL B RUBINSTEIN
• 金额: $ 7.45万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3078719
• 关键词: B lymphocyte; Epstein Barr virus; aging; antinuclear autoantibody; autoimmune disorder; bone marrow; cell senescence; cell transformation; gene expression; gene frequency; gene rearrangement; genetic library; genetic mapping; human old age (65+); human subject; immunoglobulin genes; immunoglobulin structure; leukocyte activation /transformation; molecular cloning; nucleic acid probes; nucleic acid sequence; polymerase chain reaction; pulsed field gel electrophoresis; rheumatoid factor

There is substantial evidence that the aging immune system undergoes a variety of changes in both T cell and B cell function. Characteristically, senescent immunity in the elderly show both aberrant responses to common non-self antigens as well as production of a number of anti-self autoantibodies, even among those individuals without overt autoimmune disease. These apparent changes in immunoglobulin production are no doubt multi-factorial, but studies into the immunoglobulin repertoire of B cells giving rise to them will answer several fundamental questions about that repertoire and its changes with age. Although a great deal has been learned about the organization and rearrangement of the immunoglobulin heavy chain variable region (VH) gene, the expression of individual genes has until now been difficult to analyze. We have studied the VH genes of two human anti-DNA antibodies and shown that oligonucleotide probes from the most variable part of the gene, the complementarity determining regions (CDR), detect a very limited number of genes and that combined information from two CDRs identify individual, single genes in both germline and expression studies. Preliminary studies have shown that some VH genes may be overexpressed as compared to others. The group of overexpressed genes was seen to be highly related(greater than 98% homology) to each other in both CDR and framework regions. We propose to expand these findings and apply these methods of study of V gene expression in answer to some of the following questions: (1) Does the immune repertoire differ in the older, senescent immune system as compared to that in a young individual, or even between older individuals with and without overt autoimmune disease? (2) Is the frequency of expression of individual VH genes correlated with the frequency of rearrangement in bone marrow or does selection plays a dominant role in the expressed repertoire of the three types of individuals under study? (3) What is the mechanism of overexpression of certain VH genes: is it due to a (large) family of closely-related germline genes or to preferential expression of a single germline gene.(4) Test whether 'natural' non-pathogenic autoantibodies in the elderly are encoded by highly conserved, frequently-expressed V genes while autoantibodies from older individuals with overt autoimmune disease are encoded by less well conserved or less frequently expressed V genes.

有大量证据表明，衰老的免疫系统会经历 T细胞和B细胞功能的多种变化。 特点是， 老年人的衰老免疫力表现出对常见的两种异常反应 非自身抗原以及许多抗自身抗原的产生 自身抗体，即使是那些没有明显自身免疫的个体 疾病。 免疫球蛋白产生的这些明显变化无疑是 多因素，但研究的是 B 细胞的免疫球蛋白库 引起它们将回答有关的几个基本问​​题 曲目及其随年龄的变化。 尽管我们对这个组织和组织有了很多了解 免疫球蛋白重链可变区（VH）基因的重排， 迄今为止，单个基因的表达仍难以分析。 我们研究了两种人类抗DNA抗体的VH基因并显示 寡核苷酸探针来自基因最可变的部分， 互补决定区（CDR），检测数量非常有限的 基因和来自两个 CDR 的组合信息可以识别个体， 种系和表达研究中的单基因。 初步研究 已经表明，与其他基因相比，某些 VH 基因可能过度表达。 过度表达的基因组被认为是高度相关的（大于 CDR 和框架区彼此具有 98% 同源性）。 我们建议 扩展这些发现并应用这些 V 基因研究方法 回答以下一些问题的表达式： (1) 与较老、衰老的免疫系统相比，免疫组库有所不同 年轻人之间，甚至老年人之间 没有明显的自身免疫性疾病？ (2) 的表达频率 个体VH基因与骨重排频率相关 本质还是选择在表达的全部内容中起主导作用 所研究的三种类型的个体是什么？ (3) 其作用机制是什么 某些 VH 基因的过度表达：是否是由于（大）家族 密切相关的种系基因或单个基因的优先表达 种系基因。(4) 测试是否存在“天然”非致病性自身抗体 老年人由高度保守、频繁表达的 V 基因编码 而来自患有明显自身免疫性疾病的老年人的自身抗体 由保守性较差或表达频率较低的 V 基因编码。