Determining the effects of aging on the splenic marginal zone and the implications for host immunity

脾的边缘区域是一个特殊的组织环境，在捕获和清除血流中的病原体方面发挥着重要作用。免疫反应受年龄的影响很大，这个过程被称为“免疫衰老”。尽管许多研究已经解决了与年龄相关的全身免疫反应的变化，如对T细胞和胸腺的免疫反应，但关于衰老对边缘地带的影响以及这种影响如何影响免疫，人们知之甚少。因此，人们对老年人免疫功能下降的机制知之甚少。超过26%的英国人口年龄在65岁以上。然而，尽管预期寿命和医疗保健有所进步，但老龄化与免疫衰老、机会性感染、癌症和炎症性疾病的发生率和严重性增加以及疫苗接种效果下降有关。这些问题说明了旨在了解导致免疫衰老的因素的研究的重要性。肺炎链球菌感染引起的侵袭性肺炎是65岁以上人群死亡的主要原因，老年人对这种疾病的疫苗效力降低。边缘带缺陷与肺炎球菌疾病风险升高和抗体反应差有关。这表明，衰老对脾边缘地带的影响可能同样会影响老年人对血液中病原体的有效抗体反应的能力。我们的新发现表明，在老年脾中，脾边缘区域的组织被扰乱，显著阻碍了对血流中颗粒的采样能力。这些数据揭示了免疫系统对血流进行病原体采样的能力中与衰老有关的一个重要缺陷。与衰老相关的免疫功能下降意味着疫苗对老年人的效果较差。对与衰老相关的MZ状态急剧下降的细胞和分子机制进行彻底分析，将有助于确定增加系统性感染易感性和降低肺炎球菌疾病疫苗效力的因素，并找到提高老年动物和人类免疫力的新方法。因此，在这项研究中，我们的目标是全面描述衰老对脾边缘区域细胞的影响，确定这种影响背后的分子和细胞因素，并探索增强老年动物和人类对血液传播病原体的免疫反应的潜在方法。

The marginal zone of the spleen is a specialised tissue environment that plays an important role in the capture and clearance of pathogens from the blood-stream. The immune response is significantly affected by ageing, a process termed 'immunosenescence'. Although many studies have addressed the age-related changes to systemic immune responses such as those to T cells and the thymus, little is known of the effects of aging on the marginal zone and how this affects immunity. As a consequence, the mechanisms underlying this decline in immune function in the elderly are poorly understood. More than 26% of the UK population is over 65 years old. However, despite life-expectancy and healthcare advances, aging is associated with immunosenescence and the increased incidence and severity of opportunistic infections, cancer and inflammatory diseases, and the decreased efficacy of vaccinations. These issues illustrate the importance of studies aimed at understanding the factors which cause immunosenescence. Invasive pneumococcal disease from Streptococcus pneumonia infection is a leading cause of mortality in people over 65 years old, and the effictiveness of vaccines against this disease are decreased in the elderly. Marginal zone deficiencies are associated with elevated risk of pneumococcal disease and poor antibody responses. This suggests that effects of aging on the marginal zone of the spleen may likewise affect the ability of the elderly to mount effective antibody response to pathogens in the blood-stream. Our novel findings show that the organization of the marginal zone of the spleen is disturbed in the aged spleen, significantly impeding the ability to sample the particles in the blood-stream. These data reveal an important, aging-related defect in the immune system's ability to sample the blood-stream for pathogens. The ageing-associated decline in immune function means that vaccines are less effective in the elderly. A thorough analysis of the cellular and molecular mechanisms that underpin the dramatic aging-related decline in the MZ status will help identify the factors that enhance susceptibility to systemic infections and reduce the efficacy of vaccines such as those against pneumococcal disease, and identify novel approaches to improve immunity in aged animals and humans. Therefore, in this study we aim to fully characterise the effects of aging on the cells in the marginal zone of the spleen, identify the molecular and cellular factors which underlie such effects, and explore potential approaches to enhance immune responses to blood-borne pathogens in elderly animals and humans.