MABRA stands for Multi-scale Analysis of B cell Responses in Ageing
(for less technical summary see here)
Technical summary: The aged immune system loses efficacy and specificity, resulting in significant morbidity and mortality. In older age groups less specific antibodies are produced in response to infection and vaccination, and more non-specific and autoreactive antibodies are present in the circulation. We have shown that the B cell repertoire is changed with age – having a decreased diversity of Ig genes and altered subsets of B cells. In all ages we show that the human immune response is not limited to a few specific antibodies but is diverse within the individual and varies between individuals. However, there are some common features of Ig genes, in the CDRH3 region, that are favoured in a response regardless of the type of challenge. In naïve B cells the baseline features of Ig genes before challenge show age-related differences that might contribute to reduced efficacy of responses in old age. Our observations challenge the lock and key hypothesis of antibody binding and highlight the requirement for more complex models of antibody responses.
We will investigate possible mechanisms behind age-related B cell change by using data on repertoire shift at the molecular and cellular levels to build and test models of repertoire responses to challenge. Since Ig gene specificity has a central role in repertoire selection, a large part of our work centres on predicting and testing antibody binding characteristics. In addition we have unique access to mass cytometry in order to clarify some of the confusion that exists with respect to cellular phenotypes and age-related changes. Each member of this team has expertise complementary to the others such that the team is uniquely placed to address this question. The novel experimental analyses of high throughput sequencing (HTS) and mass cytometry (CyTOF) have, and will, generate a large amount of data that needs to be efficiently explored for extraction of specific age-related immune response fingerprints. Structural bioinformatics will help in the analysis and predictions of the conformational changes and binding specificity observed in the age-specific repertoire. Statistical mechanics can relate end point observation to parameters controlling microscopic stochastic events, and therefore may be usefully employed to help elucidate the reasons for differences in repertoire with age.
Faculty of Health and Medical Sciences, Duke of Kent Building, University of Surrey,
Guildford, GU2 7XH