The IMMaged study: understanding the balance of immunity and immune disease in an aged immune system

Our immune systems change as we get older, resulting in weaker protective responses to vaccines and infections and at the same time increasing 'autoimmune' responses in which the body reacts against itself, causing unhelpful inflammation or disease. We know these changes occur, but not what makes them happen or how we might improve them when they do. A better understanding of immune ageing could allow us to design better vaccines, identify who needs them most or better treat inflammatory disease in older people. To understand how the immune system works differently in older people, it is first necessary to describe the changes occurring: in other words, to find out what 'normal' ageing looks like. As part of an international effort, we have carefully collected and measured many different aspects of the immune system in thousands of people to describe what changes occur. This included measures of different cell types and protein levels in the blood alongside levels of protection against infection and against the body's own proteins (the 'autoreactive' responses). From this study we found that immune ageing occurred much more rapidly after 70 years of age and also changed at different rates in different people. This meant that people of a given age could have very different immune ages. We also found that their immune age was linked to their lifespan, suggesting that immune age might be critical for keeping us healthy in later years. Of all the immune changes we measured, only a few were strongly linked to immune age. We have now used this information to design a much more detailed experiment, aiming to understand more about what might be responsible for immune ageing. We want to understand in detail what happens in immune ageing. To do this, we plan to focus on people who have the same age, but very different immune ages.
We want to understand not only what is different between them, but also how their immune systems respond differently to the same 'challenge'. To do this we will identify two groups of people with similar ages but very different immune ages and take blood samples before, during and after they receive their standard influenza and COVID booster vaccinations: we only need take blood samples while they have booster shots just as they would do in any case. From the blood samples we will purify a range of different immune cell types - both those we have linked to immune age and others likely to contribute. We can then analyse these immune cell populations in minute detail, measuring for each individual cell which genes are switched on, which proteins are present and the type of antibody or immune receptors they use. This is helpful as the level of detailed information generated allows us to identify the cells linked to 'older' immune responses, even those we may not have suspected were important (as we can measure all genes in every cell). We can also use this information to work out how cells are responding differently in the two groups of people. We can do this at each timepoint of the experiment (for example, before they get their vaccine) but we can also look at changes occurring over time, comparing before and after vaccination. After they receive their vaccine we will measure how effective a response they have made and also the extent to which they have produced an 'incorrect' response against their own body's proteins.
By putting together all of this information we aim to identify changes in immune ageing that control the balance between helpful and harmful immunity. We believe this is the first step towards a better understanding of how medications should be used in the elderly to influence that balance: improving older peoples' ability to fight infection, cancer and to respond to vaccines and improving our ability to treat inflammatory disease also. This could have a huge impact on the duration and quality of life in ageing.

Changes in the immune system occurring with increasing chronological age are manifest as an increased susceptibility to infection, reduced responses to vaccination, a persistent state of low-level inflammation and a greater tendency toward autoimmune responses. Together, these changes may be termed 'immune ageing'. This proposal builds on our previous work systematically characterising, for the first time at scale in thousands of samples, the cross-sectional and longitudinal genomic changes characterising immune ageing. This analysis included changes in cell number and proportion, protein expression, antigen receptor usage and in antibodies against both self and pathogen derived antigens. By integrating these data we have identified non-linear changes occurring with increasing age, characterised by increasing autoreactivity, limited antigen receptor repertoire diversity and an expansion of IgM+ IgD+ memory B cells from which pathogen-specific responses are increasingly derived. We can use these changes to quantify immune age independent of chronological age, measuring relative to the age-adjusted population value. An individual's immune age is associated with future clinical outcome but not comorbidity at the time of sampling indicating relevance in shaping health in ageing. This proposal - the ImmAged study - aims to deeply characterise the immune response to standardised vaccine challenge in selected individuals matched for chronological age but with polarised immune ages. We will sample inviduals before, during and after vaccination against influenza and SARS-CoV-2 using multi-omic profiling of their antigen-specific and global immune response at single cell level. The study is designed to compare cell subpopulations and their differentiation trajectories with the goal of better understanding the mechanisms and pathways responsible for immune ageing as the basis to ultimately prevent or alleviate the resulting pathological effects.