Determining the effects of ageing on the innate mucosal immune system

肠道粘膜免疫系统在抵抗食源性和吸入性病原体及其毒素方面起着重要作用。超过26%的英国人口年龄在65岁以上，预计在未来几十年内将大幅上升。肠道和呼吸道的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，如脾脏和胸腺中的免疫反应，但粘膜免疫系统很少受到关注。因此，对老年人肠道免疫功能下降的机制知之甚少。肠道感染、癌症、炎性疾病的发病率和严重程度与年龄相关的显著增加，加上疫苗接种效力的降低，说明了旨在了解这种免疫衰老所涉及因素的研究的重要性。事实上，老年人肠道病原体的死亡率大幅增加。类似地，呼吸道病原体流感病毒和肺炎链球菌也在老年人中引起显著的发病率和死亡率，并且针对它们的疫苗接种在老年人中的效果要差得多。改善老年人的保护措施也是世界卫生组织的一个主要公共卫生优先事项。肠道中分泌一种特定类型的抗体分子（分泌伊加），有助于保护肠道免受细菌毒素和病原微生物感染。与年龄相关的肠道免疫应答下降损害了肠道中的伊加应答。然而，受衰老影响的粘膜免疫系统内的精确阶段、细胞和分子尚不清楚。本提案中描述的研究旨在详细研究宿主年龄对小肠和大肠粘膜免疫系统状态和功能的影响。 肠道内层（上皮）中的一种特殊类型的细胞称为M细胞，专门用于对肠道内容物进行采样，以允许粘膜免疫系统对肠道内的病原体或毒素产生适当的免疫反应。在没有M细胞的情况下，粘膜免疫应答不太有效。尽管M细胞在粘膜免疫中起着重要作用，但对衰老对其功能的影响一无所知。我们的新发现表明，老年动物肠道中M细胞的功能显著降低，显著阻碍了它们对肠道内容物进行采样的能力。我们也有证据表明，这些细胞在上呼吸道粘膜免疫系统中受到不利影响。这些数据揭示了粘膜免疫系统监测摄入和吸入病原体的能力中一个重要的、以前未被认识到的、与衰老相关的缺陷。与年龄相关的免疫功能下降意味着疫苗对老年人的有效性降低。因此，鉴定在老化粘膜免疫系统中受影响的精确细胞和分子因子对于开发粘膜疫苗和有效策略以改善老年动物和人类的肠道免疫至关重要。因此，在这项研究中，我们的目标是充分验证衰老对M细胞的影响，确定这种影响的分子和细胞因素，并探索潜在的方法来提高老年动物和人类的M细胞成熟和粘膜免疫反应。鉴定引起免疫衰老的因素对于开发粘膜疫苗以提高老年动物和人类的免疫力至关重要，这将最终降低死亡率、发病率和对抗生素的依赖以治疗某些重要的细菌感染。

The mucosal immune system in the intestine plays an important role in protection against food-borne and inhaled pathogens and their toxins. Over 26% of the UK population is >65 years old and this is expected to rise significantly in future decades. The immune response in the intestine and respiratory tract 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 in the spleen and the thymus, the mucosal immune system has received little attention. As a consequence, the mechanisms underlying the decline in immune function in the intestines of the elderly are poorly understood. The significant age-related increases in the incidence and severity of intestinal infections, cancer, inflammatory diseases, coupled with decreases in the efficacy of vaccinations, illustrate the importance of studies aimed at understanding the factors involved in this immunosenescence. Indeed, mortality from intestinal pathogens is substantially increased in the elderly. Similarly the respiratory pathogens influenza virus and Streptococcus pneumoniae also cause significant morbidity and mortality in the elderly, and vaccinations against them are much less effective in the elderly. Improving protective measures in the elderly is also a major public health priority for the World Health Organisation. A specific type of antibody molecules are secreted in the intestine (secretory IgA) and help to protect the intestine against bacterial toxins and infection by pathogenic microorganisms. The ageing-associated decline in the intestinal immune response impairs the IgA response in the intestine. However, the precise stages, cells and molecules within the mucosal immune system that are affected by ageing are not known. The research described in this proposal aims to study in detail the effects of host age on the status and function of the mucosal immune system in both the small and large intestines. A special type of cells in the lining of the intestine (the epithelium) known as M cells, are specialised to sample the contents of intestine to allow the mucosal immune system to generate an appropriate immune response to the pathogens or toxins within in. In the absence of M cells, mucosal immune responses are less effective. Despite the important role of M cells in mucosal immunity, nothing was known about the effects of aging on their function. Our novel findings show that the function of M cells in the intestines of aged animals is dramatically reduced, significantly impeding their ability to sample the contents of the intestine. We also have evidence that these cells are adversely affected in the mucosal immune system of the upper respiratory tract. These data reveal an important, previously unrecognised, aging-related defect in the mucosal immune system's ability to monitor for ingested and inhaled pathogens. The ageing-associated decline in immune function means that vaccines are less effective in the elderly. The identification of the precise cellular and molecular factors affected in the ageing mucosal immune system is therefore crucial for the development of mucosal vaccines and effective strategies to improve intestinal immunity in aged animals and humans. Therefore, in this study we aim to fully characterise the effects of aging on M cells, identify the molecular and cellular factors which underlie such effects, and explore potential approaches to enhance M-cell maturation and mucosal immune responses in elderly animals and humans. Identification of the factors which cause immunosenescence is crucial for the development of mucosal vaccines to improve immunity in elderly animals and humans, which will ultimately reduce mortality, morbidity and the reliance on antibiotics to treat certain important bacterial infections.