The immune system is a complex system, made up of many different types of cells and molecules that interact together to protect us from infectious disease. It has to be able to recognise the many different foreign entities that we come across but without reacting to "self". Hence it is a system that is in very careful balance. With age this balance is disturbed, we become more prone to infectious disease (and when we catch a disease we are more poorly as a result). Vaccination, that normally we rely on to help protect us from disease, does not work as well. On the other hand we also are more likely to suffer from inflammation, and diseases where inflammation may have a part in their aetiology such as cardiovascular disease and Alzheimer's disease. Hence understanding why the older immune system fails with age is a big challenge. When we are vaccinated the immune system makes antibodies, which bind to the foreign molecule (antigen), have a variety of functions and are the chief readout for many vaccines to decide if the vaccine has worked or not. The antibodies are made by B cells, and after vaccination we are left with memory B cells that know how to make the antibodies we need in case we meet the disease we were vaccinated against. In old age we make less effective antibodies, and some of the antibodies that we do have react to "self" antigens. So somewhere in the antibody - generation process the balanced system has changed. We have shown that some types of B cell are changed with age, but we don't know what their function is. We will use our unique cell analyser (capable of measuring 35 different parameters per cell) to identify exactly which types of B cell are changed with age. We have also previously shown that in older people the repertoire of the antibody-producing cells is less diverse. This loss of diversity is associated with poor health. Diversity is important in a vaccine response, as sequencing of thousands of antibody genes in a response shows that many different types of antibody genes are involved. However, we also found that within a population of responding cells there are favoured characteristics of a section of the antibody gene (CDRH3) which codes for the part of the antibody that is important in binding the foreign antigen. So even though the response looks diverse, there are some common sequence characteristics between antibodies - even for different foreign antigens. We hypothesise that favoured CDRH3 characteristics are ones that make a structure that is capable of binding to multiple foreign antigens (polyspecific), and that these will predominate in a vaccine challenge. However, there needs to be a limit on polyspecificity as this could lead to self-reactivity - we could make an antibody to a foreign pathogen but it might accidentally also bind to a self-antigen and cause autoimmune disease. Since lack of foreign antigen specificity and gain of self-reactivity are features of antibodies from older people, the balanced trade-off between the advantages and disadvantages of polyreactivity may be disturbed in old age. Many other factors are involved in a vaccine response, and we don't know the details of them all. Hence we will use statistical mechanics to make a model of the B cell response, enabling us to look at events on a population level without knowing the detailed interactions below it. We will model the dynamics of a B cell response, incorporating values determined from laboratory investigation. The data will be carefully looked at to define values for CDRH3 characteristics that might be polyspecific, and we will produce some antibodies in the lab to test our predictions of whether a given CDRH3 sequence would be polyspecific or not. We hope that production and validation of a model that explains the balance between foreign antigen specificity and self-reactivity will then enable us to focus on factors that we might change to redress the balance in older age.