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Mechanism of Autoantibody Formation in Human Aging

人类衰老中自身抗体形成的机制

基本信息

批准号：
6641207
负责人：
BERNARD D STOLLAR
金额：
$ 23.78万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-15 至 2006-07-31
项目状态：
已结题

项目摘要

The long term goal of the proposed research is to understand aging-associated changes in autoantibody formation and humoral responses to vaccination. In the current period of this grant support, we have confirmed the increased frequency of autoantibody production, identified changes in the expressed Ig gene repertoire in human aging, and found a high degree of variability among elderly humans in frequency of Ig gene mutations and in the memory B cell numbers. We will pursue the implications of these findings, both in continuing studies on the origins of aging-associated autoantibodies and in tests of the functional significance of variations in memory B cell numbers. Specific Aim 1. We will continue to test alternate hypotheses for mechanisms underlying autoantibody formation, to distinguish between unmasked expression of natural autoantibodies and autoantigen-stimulated selection. Specific Aim 2: We will test the hypothesis that marked deviations from normal numbers of CD27+ memory B cells predict a poor response of nursing home residents to influenza vaccination and that their memory B cell changes are related to underlying changes in T cell functions. We will determine: a. whether CD19+CD27+ cells correspond to memory B cells, with mutated V region genes, in elderly people as in young adults; b. whether the size of the CD27+ memory B cell population is a fixed characteristic for individuals, or a labile parameter that may reflect disease or diminished regulation; c. whether influenza-specific memory B cells are present among the CD27+ B cells of vaccinated subjects; d. Whether unusually low or high levels of CD27+ B cells are correlated with unusual levels of T cell subset populations and/or low T cell function, which might underlie B cell dysregulation; and e. whether nursing home residents with either very low or very high numbers of memory B cells generate a low humoral response to influenza vaccine.

这项研究的长期目标是了解与年龄相关的自身抗体形成和对疫苗接种的体液反应的变化。在本研究资助的当前阶段，我们已经证实了自身抗体产生频率的增加，确定了人类衰老过程中表达的IG基因库的变化，并发现老年人中IG基因突变频率和记忆B细胞数量的高度变异性。我们将继续研究这些发现的意义，包括与衰老相关的自身抗体的起源，以及记忆B细胞数量变化的功能意义。具体目标1.我们将继续测试自身抗体形成机制的替代假设，以区分天然自身抗体的未掩蔽表达和自身抗原刺激的选择。具体目标二：我们将检验这一假设，即CD27+记忆B细胞的正常数量的显著偏离预测疗养院居民对流感疫苗接种的反应较差，以及他们的记忆B细胞变化与T细胞功能的潜在变化相关。我们将确定：a.在老年人和年轻人中，CD 19 + CD 27+细胞是否对应于具有突变的V区基因的记忆B细胞; B.所述CD27+记忆B细胞群体的大小是个体的固定特征还是可反映疾病或减弱的调节的不稳定参数; c.流感特异性记忆B细胞是否存在于接种疫苗的受试者的CD27 + B细胞中; d.异常低或高水平的CD 27 + B细胞是否与异常水平的T细胞亚群和/或低T细胞功能相关，这可能是B细胞失调的基础;以及e.记忆B细胞数量非常低或非常高的疗养院居民是否对流感疫苗产生低体液应答。