IMMUNE SENESCENCE AUTOIMMUNITY AND AGING

有大量证据表明，老化的免疫系统经历了 T细胞和B细胞功能的各种变化。从特征上讲， 老年人的衰老免疫表现出对常见的 非我抗原以及产生的一些抗我抗体 自身抗体，即使在那些没有明显自身免疫的个体中也是如此 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细胞免疫球蛋白谱系的研究 它们的产生将回答与此有关的几个基本问题 曲目及其随年龄的变化。 尽管已经了解了很多关于该组织和 免疫球蛋白重链可变区基因重排， 到目前为止，单个基因的表达一直很难分析。 我们已经研究了两种人类抗DNA抗体的vh基因，并显示出 这种寡核苷酸探测基因最易变的部分，即 互补决定区(CDR)，检测到数量非常有限的 基因和来自两个CDR组合信息识别个体， 在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，一些VH基因可能过度表达。 这组过度表达的基因被认为高度相关(大于 CDR和骨架区域的同源性均为98%)。我们建议 扩大这些发现，并应用这些方法研究V基因 表达对以下一些问题的回答：(1) 与之相比，较老的、衰老的免疫系统的免疫系统有所不同 在年轻人身上，甚至在年长的人和 无明显自身免疫性疾病？(2) 单个VH基因与骨骼中重排的频率相关 骨髓还是选择在表达的谱系中起主导作用？ 被研究的三种类型的个体是什么？(3)是什么机制 某些VH基因的过度表达：是不是由于一个(大)家族 亲缘关系密切的生殖系基因或对单个基因的优先表达 生殖系基因。(4)检测“天然”非致病性自身抗体在 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 是由保守程度较低或表达频率较低的V基因编码的。

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.