Mechanism of Autoantibody Formation in Human Aging

拟议研究的长期目标是了解与年龄相关的自身抗体形成变化和疫苗接种的体液反应。在目前的资助期内，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。我们将继续研究衰老相关自身抗体的起源，以及记忆B细胞数量变化的功能意义。具体目标我们将继续测试自身抗体形成机制的其他假设，以区分天然自身抗体的暴露表达和自身抗原刺激的选择。特异性目标2：我们将验证一个假设，即CD27+记忆B细胞数量明显偏离正常水平，预测养老院居民对流感疫苗的不良反应，他们的记忆B细胞变化与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+细胞是否与V区基因突变的记忆B细胞相对应；B . CD27+记忆B细胞群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.接种者的CD27+ B细胞中是否存在流感特异性记忆B细胞；d.异常低或异常高水平的CD27+ 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；e.记忆B细胞数量非常低或非常高的养老院居民对流感疫苗的体液反应是否很低。

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.