PDF(Pubmed)
Abstract：
The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.
摘要：
新生儿免疫系统与老年个体的免疫系统不同,这使得新生儿易受感染并且对疫苗接种反应较差。佐剂可用作增强对共同施用的抗原的免疫应答的工具。抗体（Ab）持久性是由长期存活的浆细胞介导的，这些浆细胞存在于骨髓中的专门存活壁ni中，生命早期的瞬时Ab反应与浆细胞的存活率降低有关，可能是由于缺乏生存因素。各种细胞可以分泌这些因子，哪些细胞是主要的生产者仍在争论中，尤其是在早期生活中，这个问题还没有得到充分解决。受体BCMA及其配体APRIL已显示在浆细胞和Abs的维持中重要。在这里，我们评估了大范围骨髓附属细胞的年龄依赖性成熟及其存活因子APRIL和IL-6的表达.此外，我们对5种不同佐剂的潜力进行了比较分析；LT-K63，mmCT，MF59，IC31和明矾，用破伤风类毒素（TT）疫苗免疫新生小鼠后，增强存活因子和BCMA的表达。我们发现年轻小鼠骨髓中APRIL表达降低，而IL-6表达更高。嗜酸性粒细胞,巨噬细胞，巨核细胞,单核细胞和淋巴细胞是生命早期生存因子的重要分泌者，但不确定的细胞也构成了很大一部分分泌者。免疫和佐剂增强了APRIL表达，但在免疫后早期降低了骨髓细胞中IL-6的表达。此外，新生儿用佐剂免疫可提高脾脏和骨髓中表达BCMA的成浆细胞和浆细胞的比例。增强的BCMA表达与增强的疫苗特异性体液应答相关，即使明矾对BCMA的影响在稍后的时间点不如其他佐剂明显。我们认为，骨髓中的低APRIL表达以及早期成浆细胞/浆细胞的低BCMA表达共同导致短暂的Ab反应，并且可能代表疫苗佐剂触发的靶标，以诱导该年龄段的持续体液免疫反应。
