Krichevsky Svetlana, Pawelec Graham, Gural Alexander, Effros Rita B, Globerson Amiela, Yehuda Dina Ben, Yehuda Arie Ben
Department of Medicine, Hadassah University Hospital, POB 12000, Jerusalem 91120, Israel.
Exp Gerontol. 2004 Apr;39(4):507-15. doi: 10.1016/j.exger.2003.12.016.
Many immune functions decline with age and may jeopardize the elderly, as illustrated, for example by the significantly higher mortality rate from influenza in old age. Although innate and humoral immunity are affected by aging, it is the T cell compartment, which manifests most alterations. The mechanisms behind these alterations are still unclear, and several explanations have been offered including thymic involution and Telomere attrition leading to cell senescence. Age related accumulation of mutations has been documented and could serve as an additional mechanism of T cell dysfunction. One effective repair mechanism capable of rectifying errors in DNA replications is the mismatch repair (MMR) system. We previously reported a comparative examination of individual DNA samples from blood cells obtained at 10 year intervals from young and old subjects. We showed significantly higher rates of microsatellite instability (MSI), an indicator of MMR dysfunction in older subjects, compared to young. In the present study we confirm this result, using direct automated sequencing and in addition, we demonstrate that as CD8 lymphocytes from aged individuals, undergo repeated population doublings (PDs) in culture, they develop MSI. CD4 clones that also undergo repeated PDs in culture develop significant MSI as well. Elucidation of this previously unexplored facet of lymphocyte dynamics in relation to aging may help identify novel mechanisms of immunosenescence and pathways that could serve as targets for interventions to restore immune function.
许多免疫功能会随着年龄增长而衰退，这可能会危及老年人的健康，例如，老年人因流感导致的死亡率显著更高就说明了这一点。虽然固有免疫和体液免疫都会受到衰老的影响，但T细胞区室受到的影响最为明显。这些变化背后的机制仍不清楚，人们提出了几种解释，包括胸腺退化和端粒磨损导致细胞衰老。与年龄相关的突变积累已有文献记载，这可能是T细胞功能障碍的另一种机制。一种能够纠正DNA复制错误的有效修复机制是错配修复（MMR）系统。我们之前报告了一项对年轻和老年受试者每隔10年采集的血细胞个体DNA样本的对比研究。我们发现，与年轻人相比，老年人中微卫星不稳定性（MSI）的发生率显著更高，微卫星不稳定性是错配修复功能障碍的一个指标。在本研究中，我们使用直接自动化测序证实了这一结果，此外，我们还证明，老年个体的CD8淋巴细胞在培养中经历多次群体倍增（PDs）时会出现微卫星不稳定性。在培养中也经历多次群体倍增的CD4克隆也会出现显著的微卫星不稳定性。阐明淋巴细胞动力学这一与衰老相关的此前未被探索的方面，可能有助于识别免疫衰老的新机制以及可作为恢复免疫功能干预靶点的途径。
