The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function
The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function
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DOI：
10.1189/jlb.0804449
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发表时间：
2005-04-01
影响因子：
5.5
通讯作者：
Bondada, S
中科院分区：
文献类型：
--
作者：
Chelvarajan, RL;Collins, SM;Bondada, S
随着年龄的增长，巨噬细胞 (M Phi) 功能的降低使得小鼠对细菌荚膜多糖的反应减弱，例如肺炎球菌多糖疫苗中的细菌荚膜多糖，这是胸腺非依赖性 (TI) 抗原 (Ag) 的模型。使用三硝基苯酚 (TNP)-脂多糖 (LPS) 和 TNP-Ficoll（另外两种经过充分研究的 TI Ag），我们研究了老年人 M Phi 功能降低的机制基础。我们发现老年小鼠对这些 TI Ag 的反应严重低下。由于需要 M Phi，来自年轻成年小鼠的高度纯化的 B 细胞不会对 TI Ag 产生反应。当纯化后，用 TNP-Ficoll 免疫年轻的 B 细胞时，用老年小鼠 M Phi 重建的培养物产生的抗体明显低于用年轻 M Phi 观察到的抗体。因此，这种无反应性可以通过白细胞介素(IL)-Iβ和IL-6的混合物来克服。在用 LPS 刺激后，与年轻的 M Phi 相比，老年 M Phi 分泌的 IL-6、肿瘤坏死因子 α、IL-1 β 和 IL-12（B 细胞响应 TI Ag 所必需的细胞因子）量减少。 LPS 还诱导衰老的 M(D 产生过量的 IL-10。IL-10 的中和增强了 LPS 刺激后 M Phi 产生促炎性细胞因子，并且还诱导衰老的脾细胞产生 Ab。因此，衰老的 M(D 无法帮助 B 细胞反应似乎是由过量的 IL-10 引起的。由于衰老的 M(D 表达 Toll 样受体 4 和 CD14 的细胞数量减少，细胞因子产生的不平衡部分原因可能是表达 LPS 受体复合物关键成分的细胞较少。
A reduction in macrophage (M Phi) function with aging makes mice less responsive to bacterial capsular polysaccharides, such as those present in the pneumococcal polysaccharide vaccine, a model of thymus independent (TI) antigen (Ag). Using trinitrophenol (TNP)-lipopolysaccharide (LPS) and TNP-Ficoll, two other well-studied TI Ag, we studied the mechanistic basis of reduced M Phi function in the aged. We show that aged mice are profoundly hyporesponsive to these TI Ag. As a result of a requirement for M Phi, highly purified B cells from young-adult mice do not respond to TI Ag. When purified, young B cells were immunized with TNP-Ficoll, the antibody production from those cultures reconstituted with M Phi from aged mice was significantly lower than that seen with young M Phi. Consequently, this unresponsiveness can be overcome by a mixture of interleukin (IL)-I beta and IL-6. Upon stimulation with LPS, in comparison with young M Phi, aged M Phi secreted reduced amounts of IL-6, tumor necrosis factor alpha, IL-1 beta, and IL-12, cytokines necessary for B cells to respond to TI Ag. LPS also induced aged M(D to produce an excess of IL-10. Neutralization of IL-10 enhanced the production of proinflamatory cylokines by M Phi upon LPS stimulation and also induced Ab production by aged splenocytes. Thus, the inability of aged M(D to help the B cell response appears to be caused by an excess of IL-10. As aged M(D have a reduced number of cells expressing Toll-like receptor 4 and CD14, the imbalance in cytokine production might be partly a result of fewer cells expressing key components of the LPS receptor complex.