Determining the effects of ageing on the innate mucosal immune system

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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.