IMMUNE SENESCENCE, AUTOIMMUNITY, AND AGING

免疫衰老、自身免疫和衰老

• 批准号: 2048265
• 负责人: DANIEL B RUBINSTEIN
• 金额: $ 7.66万
• 依托单位: BOSTON 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: 1991-12-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2048265
• 关键词: B lymphocyte; Epstein Barr virus; aging; antinuclear autoantibody; autoimmune disorder; autoimmunity; 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，衰老的免疫系统经历了一个 T细胞和B细胞功能的各种变化。 典型地， 老年人的衰老免疫表现出对常见的 非自身抗原以及大量抗自身抗体的产生 自身抗体，即使在那些没有明显的自身免疫性 疾病 免疫球蛋白产生的这些明显变化无疑是 多因素，但对B细胞免疫球蛋白库的研究 它们的产生将回答几个基本问题 它的变化和年龄的变化。 尽管人们对该组织了解得很多， 免疫球蛋白重链可变区（VH）基因的重排， 单个基因的表达至今难以分析。 我们研究了两种人抗DNA抗体的VH基因， 从基因最可变的部分， 互补决定区（CDR），检测非常有限数量的 基因，并且来自两个CDR的组合信息识别个体， 单基因在生殖系和表达研究。 初步研究 已经表明，与其他基因相比，一些VH基因可能过表达。 这组过表达的基因被认为是高度相关的（大于 98%同源性）。 我们提出 为了扩大这些发现并应用这些研究V基因的方法， 回答下列问题：（1） 在老年人中，衰老的免疫系统与 与年轻个体的差异，甚至与老年个体的差异， 没有明显的自身免疫性疾病(2)是表达的频率 单个VH基因与骨重排频率相关 骨髓或雌激素选择在表达谱中起主导作用 研究中的三种类型的人？(3)的机制是什么 某些VH基因的过度表达：这是由于一个（大）家族， 密切相关的生殖系基因或优先表达的单一 生殖系基因(4)测试是否“天然”非致病性自身抗体， 老年人是由高度保守、频繁表达的V基因编码的， 而来自患有明显自身免疫性疾病的老年人的自身抗体 由不太保守或表达频率较低的V基因编码。