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

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.

The splenic marginal zone (MZ) is a specialised microenvironment that is important for the the capture and clearance of blood-borne pathogens/antigens. In the MZ a specialized subset of B cells (MZ B cells) is situated to capture blood-borne immune complexes and delivery them to follicular dendritic cells (FDC) in the B-cell follicles. MZ B cells also play vital roles in mounting rapid T-cell-independent (TI) antibody responses to polysaccharide antigens such as those in bacterial capsules, bridging the gap before the induction of high-affinity antibody responses. Thus, the splenic MZ is important for the sampling of blood-borne pathogens/Ag and immunity to systemic infections. We have shown that the MZ microarchitecture is grossly disturbed in aged mice impairing the ability of MZ B cells to deliver immune complexes to FDC. These data reveal an important aging-related defect in the host's ability to sample blood-borne antigens. However, nothing is known of the aging-related factors responsible for the disruption to the MZ microarchitecture, or importantly, how this impacts on immune function, especially TI-antibody responses. Invasive pneumococcal disease is a leading cause of mortality in elderly people, and the efficacy of vaccines against this disease is also decreased. As MZ B-cell deficiencies are associated with elevated risk of pneumococcal disease and poor Ab responses, this suggests that effects of aging on the MZ may likewise impact on the ability of the elderly to mount strong TI-Ab responses. A thorough analysis of the mechanisms that underpin the dramatic aging-related decline in the status of the MZ is crucial to aid our understanding of the factors that influence susceptibility to blood-borne pathogens/antigens, and to improve immunity in the elderly. Therefore, with particular emphasis on MZ B cells, this study will fully characterize the effects of aging on the splenic MZ and identify the molecular and cellular factors which underlie these defects.

Despite the important role of marginal zone B cells in immunity to T-cell-independent antigens, almost nothing is known about the effects of aging on their status and function. Therefore, many scientists will significantly benefit from the novel data generated from this proposal which address an important gap in our understanding of the effects of aging on the mucosal immune system. Scientist working in the aging field will also benefit from having access to the extremely useful resource of a range of tissues, tissue fluid, cells, DNA/RNA samples from a large number of aged mice (2 mo. old to 18 mo. old) generated from this project. In order to faciltate this, samples and data sets will be made available to interested scientist via the BBSRC-supported Shared Ageing Research Models portal and bio-bank (www.sharmuk.org).

Researchers in industry and in academia will benefit from data in this project describing the effects of aging on the maintenance and function of the marginal zone. The marginal zone is important for the development of antibody responses to T cell-independent antigens. Data describing the influence of aging on the cells within the marginal zone will aid the design of novel therapeutics, especially those which improve the efficacy of vaccines in the elderly.

UK policy makers will have interest in the project's data on an important gap in our knowledge of the effects of aging on the immune system. This may influence their assessments on the efficacy of vaccines in the elderly, or susceptibility to important systemic infections pathogens (eg: pneumococcal disease). Indeed, the applicant's recent study describing the effects of aging on TSE susceptibility (Brown et al. 2009 J. Immunol. 183, 5199) was discussed by the UK Spongiform Encephalopathies Advisory Committee.
Pharmaceutical/vaccine companies may have interest in outputs from this study. The project the applicant will consult with the Institute's Business Development and Commercialisation Department to seek potential Industry partners to exploit the project's data.

This study will enable the scientists working on the project to acquire many transferable skills in two major disciplines: in vivo immunology and aging. The scientist will also develop import skills in in vivo biology (a currently recognised research priority) and high resolution bioimaging, transcriptomics and bioinformatics. This is a collaborative. Thus, the scientist will gain opportunities to develop their team-working, networking and collaboration skills. The scientist will have many opportunities to present data at external meetings.

Data from this study will be disseminated to the international scientific community using a combination of publication in quality peer-reviewed journals and presentation at scientific meetings eg: international and national scientific conferences, seminars at other research institutions and lectures to undergraduate students. Dr. Mabbott is regularly invited to present data at these events. Indeed, he has been invited to present his data at the upcoming BBSRC-sponsored Symposium on 'Ageing: intestine, immunity, microbiota and diet'.

Dr. Mabbott is keen to explore opportunities to communicate data from this project to the public through events such as the "Doors Open" day held annually at the Institute, and also his activities as a BBSRC-funded Schools Regional Champion.

The release of potential news-worthy publications would be discussed with the Institute and BBSRC press officers and press releases issued when appropriate. Dr Mabbott's recent study on the effects of aging on FDC (Brown JImmunol 2009) was handled in such manner and covered by the international media including. Data from BBSRC grant (BB/526471/1; McCulloch 2011 PLoS Pathogens) were also featured in the media, on the BBSRC website and in BBSRC Business. Similarly, our recent S. Typhimurium study (Tahoun 2012 Cell Host & Microbe) was also featured by the media and the BBSRC.