Igh locus function in immunosenescent mice

摘要 新冠肺炎(冠状病毒传染病19)现在是一种全球大流行，有超过4910万病例。 约会。新冠肺炎是由严重急性呼吸综合征冠状病毒2型引起的成员之一 属于冠状病毒家族。令人震惊的是，80%的新冠肺炎相关死亡发生在患者身上 65岁及以上。老年人的免疫反应经历免疫衰老，表现为 多个年龄相关的变化。免疫衰老与限制性Ig谱系的形成和 对各种病毒引起的疾病的易感性。老年人特别容易患上 一系列新的和新出现的感染性病原体，可能是由于抗体谱系不那么多样化的结果。 然而，为了确定减轻免疫衰老影响的临床干预措施，关键是 描述导致静音适应的潜在环境和细胞内在机制 免疫反应。在这里，我们提出了一系列探索性的研究来检查预先选择的免疫球蛋白 年轻和老年小鼠早期和成熟B细胞的谱系建立是否存在谱系缺陷 在老年人外周血中观察到的B细胞至少部分起源于V(D)J受损 重组、类开关重组、基因座构象和/或IgH增强子功能。结果 从这一探索性项目中获得的信息将有助于a)有限的免疫球蛋白曲目多样化 在V(D)J重组和类开关重组过程中IgH基因座功能受损所致，以及 B)IgH基因座功能障碍是否是细胞固有的。

ABSTRACT COVID-19 (coronavirus infectious disease 19) is now a global pandemic with over 49.1 million cases to date. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, a member of the coronavirus family. It is striking that eighty percent of COVID-19 related deaths occur in patients aged 65 and over. Immune responses of aged adults undergo immunosenescence which expresses with multiple age dependent changes. Immune senescence is linked to restricted Ig repertoire formation and susceptibility to a variety of virally induced diseases. Older individuals are particularly vulnerable to a range of new and emerging infectious agents perhaps as a result of a less diverse antibody repertoire. However, to identify clinical interventions that mitigate the effects of immunosenescence it is critical to characterize the underlying environmental and cell intrinsic mechanisms leading to the muted adaptive immune responses. Here we propose an exploratory series of studies to examine the pre-selected Ig repertoire in early and mature B cells in young and aged mice to establish whether repertoire deficiencies observed in peripheral B cells of aged individuals originate, at least in part, from impaired V(D)J recombination, class switch recombination, locus conformation and/or Igh enhancer function. Results obtained from this exploratory project will shed light on whether a) limited Ig repertoire diversification results from impaired Igh locus function during V(D)J recombination and class switch recombination, and b) whether Igh locus dysfunction is cell intrinsic.