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

脾脏边缘区是一个特殊的组织环境，在血液中病原体的捕获和清除中起着重要作用。免疫反应受到衰老的显著影响，这一过程被称为“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细胞和胸腺的变化，但对衰老对边缘区的影响及其如何影响免疫力知之甚少。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取得了进步，但衰老与免疫衰老、机会性感染、癌症和炎症性疾病的发病率和严重程度增加以及疫苗接种效力下降有关。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。由肺炎链球菌感染引起的侵袭性肺炎球菌疾病是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下降。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，衰老对脾脏边缘区的影响可能同样会影响老年人对血液中病原体产生有效抗体反应的能力。我们的新发现表明，脾脏边缘区的组织在老年脾脏中受到干扰，严重阻碍了对血液中颗粒进行采样的能力。这些数据揭示了一个重要的、与衰老有关的免疫系统在血液中寻找病原体的能力上的缺陷。与年龄相关的免疫功能下降意味着疫苗对老年人的效果较差。对支持与年龄相关的MZ状态急剧下降的细胞和分子机制进行彻底分析，将有助于确定增加对全身性感染的易感性和降低疫苗（如肺炎球菌疾病疫苗）效力的因素，并确定提高老年动物和人类免疫力的新方法。因此，在本研究中，我们的目标是充分表征衰老对脾脏边缘区细胞的影响，确定导致这种影响的分子和细胞因素，并探索增强老年动物和人类对血源性病原体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.