Mechanism of Autoantibody Formation in Human Aging

这项拟议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。在目前的赠款支持期间，我们证实了自身抗体产生的频率增加，确定了人类衰老过程中免疫球蛋白基因表达谱的变化，并发现老年人在免疫球蛋白基因突变频率和记忆B细胞数量方面存在高度变异性。我们将在继续研究衰老相关自身抗体的起源以及测试记忆B细胞数量变化的功能意义时，继续研究这些发现的意义。具体目标1。我们将继续测试自身抗体形成的潜在机制的替代假说，以区分天然自身抗体的非掩蔽表达和自身抗原刺激的选择。具体目标2：我们将检验这样一个假设，即显著偏离正常数量的CD27+记忆B细胞预示着疗养院居民对流感疫苗接种的反应不佳，并且他们记忆B细胞的变化与T细胞功能的潜在变化有关。我们将确定：a.在老年人和年轻人中，CD19+CD27+细胞是否对应于带有V区基因突变的记忆B细胞；b.CD27+记忆B细胞群体的大小是个体的固定特征，还是可能反映疾病或调节减弱的不稳定参数；c.接种疫苗的受试者的CD27+B细胞中是否存在流感特异性记忆B细胞；d.CD27+B细胞异常低或高水平是否与T细胞亚群和/或T细胞功能低下的异常水平相关，这可能是B细胞失调的基础；以及E.无论是记忆B细胞数量非常低还是非常高的疗养院居民对流感疫苗的体液反应都很低。

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.