ONTOGENY OF GENERATION OF NEONATAL ANTIBODY DIVERSITY

描述(改编自申请人的描述)：包括不成熟的和完整的 足月人类新生儿对疫苗产生次佳抗体(Ab)反应。 这项提案的总体目标是调查 新生儿B细胞前免疫抗体谱系及其多样性的研究 免疫后的这种谱系有助于产生有缺陷的抗体反应和 孕期免疫能否改变免疫球蛋白 新生儿的谱系和B细胞记忆。在目标1中，调查人员 假设新生儿的免疫前能力受到限制 免疫球蛋白重链第三互补的多样性 决定区(CDR3)，由Ig基因片段连接而成 和N区加成。为了研究这一假设，他们将 描述和比较中国人CDR3区的多样性和结构 早产和足月新生儿及成人B淋巴细胞。他们会分析 各自表达的CDR3文库的潜在抗原结合活性 具有单一免疫球蛋白重链可变区基因(VH)的组和 Fab表面噬菌体表达文库中轻链基因与其结合 自身抗原和非自身抗原。在目标2中，我们将研究这一假设 新生儿未能使免疫后和抗体谱系多样化 从VH的体细胞超突变分析VH的体细胞超突变 新生儿出生后和免疫后。来探索这样的假设 新生儿B细胞库可以通过母体免疫来改变 在怀孕期间接种疫苗，导致高滴度克隆性 限制了免疫球蛋白抗体的反应，他们将免疫孕妇的第三 怀孕三个月接种乙型流感嗜血杆菌疫苗， 产生高效价寡克隆免疫球蛋白抗体，并分析 通过产生抗体和寻找免疫启动证据的后代 B细胞存储器的产生。这些调查的结果应该 为新生儿B细胞库的个体发育提供新的见解 以及加速免疫的可能性。

DESCRIPTION (Adapted from Applicant's Description): Both premature and full term human neonates generate suboptimal antibody (Ab) responses to vaccines. The overall goal of this proposal is to investigate whether defects in the preimmune Ab repertoire of neonatal B cells and in the diversification of this repertoire after immunization contribute to defective Ab responses and whether immunization during pregnancy is able to alter the immunoglobulin repertoire and B cell memory of the neonate. In Aim 1, the investigators hypothesize that the preimmune repertoire of the neonate is restricted in diversity of the immunoglobulin heavy chain third complementarity determining region (CDR3), which arises from the joining of Ig gene segments and N region addition. To investigate this hypothesis, they will characterize and compare the diversity and structure of the CDR3 regions of preterm and full term neonatal and adult B lymphocytes. They will analyze the potential antigen binding activity of a CDR3 library expressed from each group with a single immunoglobulin heavy chain variable region gene (VH) and light chain gene in a Fab surface phage expression library for binding to self and non-self antigens. In Aim 2, we will investigate the hypothesis that the neonate fails to diversify postimmunization and Ab repertoires with somatic hypermutation of VH by analyzing somatic hypermutation in VH at birth and after immunization of the neonate. To explore the hypothesis that the neonatal B cell repertoire can be altered by maternal immunization during pregnancy with vaccines that induces a high titered clonally restricted IgG Ab response, they will immunize pregnant women in the third trimester of pregnancy with Haemophilus influenzae b vaccines, which generate a high-titered oligoclonal IgG Ab response, and analyze the offspring for evidence of immunologic priming with Ab production and generation of B cell memory. The results of these investigations should provide novel insights into the ontogeny of the neonatal B cell repertoire and in the potential to accelerate of immunity.