THE B-CELL REPERTOIRE OF AGED MICE

衰老伴随着B细胞库的许多改变 表达和反应。 尽管老年小鼠的B细胞对 正常的T/H依赖性抗原和总体数量和多样性 当维持B细胞的免疫应答时，应答某些免疫应答的B细胞的库（repertoire）被维持。 抗原发生改变，产生高亲和力记忆B的能力 细胞受损 这是一项继续我们长期以来 研究这些衰老的细胞和分子基础 免疫应答的B细胞成分的相关改变。 虽然新生成的B细胞的数量在 在老年小鼠中，B细胞发育的途径被改变， 成熟前B细胞群减少数倍。 以确定 如果这是由于前B细胞过程中克隆扩增减少 发展，在具体目标1，我们将评估复发的独特H 各种发育B细胞亚群内细胞中的链V区 从单个股骨的骨髓中获得。 我们还将使用单 细胞PCR以确定前B细胞成熟是否可以通过 过早的L链表达。 为了确定克隆的减少是否 消除（耐受性）在老年小鼠有助于维持 正常数量的新产生的B细胞，在具体目标2中，我们将 确定是否存在SLG受体介导的消除的减少 表达由V（H）81 X-D-J（H）编码的H链的新生成B细胞 重新安排 最后，为了评估 记忆祖细胞的改变导致了 高亲和力体细胞突变记忆B细胞，在特异性目标3中，我们 将评估，克隆，记忆祖细胞的能力，从 幼稚和免疫的老年小鼠产生记忆B细胞并积累 体外体细胞突变

Aging is accompanied by numerous alterations in B cell repertoire expression and responsiveness. Although B cells of aged mice respond normally to T/H dependent antigens and the overall numbers and diversity of B cells is maintained, the repertoire of B cells responsive to certain antigens is altered and the capacity to generate high affinity memory B cells is compromised. This is a proposal to continue our long-standing investigation of the cellular and molecular basis of these aging associated alterations in the B cell component of the immune response. Although the number of newly generated B cells is not markedly reduced in aged mice the pathway of B cell development is altered such that the population of mature pre B cells is decreased several fold. To determine if this is due to a decrease in clonal expansion during pre B cell development, in Specific Aim 1 we will assess the recurrence of unique H chain V regions in cells within various developmental B cell subsets obtained from the marrow of individual femora. We will also use single cell PCR to determine whether pre B cell maturation may be accelerated by premature L chain expression. To determine if a decrease in clonal elimination (tolerance) in aged mice contributes to the maintenance of normal numbers of newly generated B cells, in Specific Aim 2 we will determine if there is a decrease in slg receptor mediated elimination of newly generated B cells that express H chains encoded by V(H)81X-D-J(H) rearrangements. Finally, to assess the potential contribution of alterations in memory progenitors to the decrease in the generation of high affinity somatically mutated memory B cells, in Specific Aim 3 we will evaluate, clonally, the capacity of memory progenitors obtained from naive and immunized aged mice to generate memory B cells and accumulate somatic mutations in vitro.