Community Research and Development Information Service - CORDIS


ImmunoAgeing Report Summary

Project ID: 633964
Funded under: H2020-EU.3.1.1.

Periodic Reporting for period 1 - ImmunoAgeing (An integrated approach to dissect determinants, risk factors and pathways of ageing of the immune system.)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

The project is designed to fill the existing gap in information by elucidating key determinants, both inherited and environmental, as well as pathways and mechanisms governing this process and its clinical hallmarks. Toward this aim the existing longitudinal and cross-sectional collections of data and samples from the general population and from patients with a variety of autoimmune diseases across a broad spectrum of ages will be exploited. The main objectives are to assess the role of quantitative variation of the immunome (including a vast range of immune cell subtypes and soluble factors) in immunosenescence, and identify genetic and modifiable environmental exposures (including smoking, diet, alcohol intake and physical activity) contributing to this variation in a large population cohort of volunteers over a broad spectrum of ages from 18 to 110. Furthermore, the project aims to assess the extent and genetic bases of the circulating autoantibodies responsible for the autoreactivity phenomena that increases during ageing and to correlate their presence with chronic viral infections; in parallel the study will assess the contraction of the B cell and T cell responsiveness that renders the elderly more prone to infections, and less responsive to vaccination.
The study evaluates the changes in the functional and transcriptional profile of those cell types that show the strongest age-related changes, and whose circulating levels are affected by known genetic variants. In general, the whole study will provide the trajectory underlying the ageing process for the age-affected traits such as soluble molecules, cell frequencies, surface markers and transcripts, and will define the usual quantitative values for specific age ranges. Interestingly, the project will define the immunological age of a given individual that could different from the chronological age being the latter a rather inaccurate surrogate of the biological age.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The study has been focused on: the impact of ageing on circulating immune cells, the impact of ageing on serum cytokines and immunoglobulins, the effect of smoke on the immune system as an environmental factor, the isolation of senescence-related immune cells to assess their functional profile and autophagy capability, as well as the assessment of disease associated autoantibodies on the “core” cohort including a vast collection of sera from the community population cohorts of the Consiglio Nazionale delle Ricerche (~4,000) and University of Cambridge (~4,000).
Overall we assessed 163 cellular traits belonging to the innate and adaptive immunity expressed as absolute counts (cells/ul) and 243 percentages with respect to hierarchically higher cell populations. These traits have been analyzed on a sample set from 1,000 to about 3,915 individuals.
The first results were obtained by comparing the age range 40-60, 61-80 and over 80 to the youngest group (18-40). To further investigate the immune system with more resolution, immunophenotypes have been analyzed in narrow age ranges of 5 years. Data showed a general decrease of the main leukocyte subset with the strongest effect on cytotoxic (CD8+CD4-) sub-classes compared to helper (CD4+CD8-) subsets. For a direct data interpretation and to avoid any confounding effect due to reciprocal effects between cell frequencies, we first focused on absolute counted cell and, in general, we observed a tendency to diminish during age. Notably, only some populations including activated lymphocytes and a subset of monocytes. To have a complete overview of the immune system during lifetime, CNR also assessed some soluble (s) serum proteins whose function is strongly related to immune cells function.
In parallel, with the aim to elucidate the functional and transcriptional properties of the cell types that show the strongest age-related changes, and whose circulating levels are affected by known genetic variants, we exploited the data emerged from correlation between immune cells and age and between immune cells and diseases. We identified and selected 4 lymphocyte subtypes to isolate for subsequent analysis. Two of them are T cell subsets that increase with age; while two are B cell subtypes that decrease with senescence and that are involved in autoimmune disease onset. We also selected diverse innate immunity populations that matched the senescence phenotype, the genetic regulation and the involvement in autoimmunity; these cellular subsets will be investigated.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Amongst the major features rendering the study particularly innovative, one is the genetic information underlying each study sample and the other is the big cohort available for sample collection and analysis. The first makes us able to narrow the sample collection to those individuals with a specific genetic background upon the experimental needs. Secondly, the use of a large cohort allows us to analyze data restricted to specific age range with a resolution and statistical power comparable to other whole-study sample set. For instance, 388 individuals are accounted for in the around 50y age interval and 153 individuals are accounted for in the between 50/103y age interval.
Furthermore, the genetic information at our disposal involved both in the regulation of the phenotypic variance and in the disease predisposition of autoimmune disease that have a clear age-related bases, allowed us to generate robust biological hypothesis on the mechanisms underlying disease predisposition. One of the recent findings illustrates an adaptive immune response to pathogens that unfortunately also leads to increased risk of autoimmunity. Very interestingly, and still in the context of human adaptation to the environment, the age and gender analyses of the soluble BAFF protein revealed that it is not affected by ageing but it is considerably affected by the gender with an increase in females compared to males (P=5x10E-18). The two autoimmune diseases MS and SLE have a strong predisposition for females with reported female:male ratio of 2.3/3.5:1 and 8/15:1, respectively. These observations inform the tight biological correlation between autoimmunity, ageing and genetic predisposition to disease predisposition and provide new tools for the development of biologically active molecules against targets responsible for the adverse effects of ageing and age-related conditions. This observation has a clear socio-economic impact given the frequency of the MS and SLE pathologies that are drastically increased over the past decades and considered the lack of suitable and specific treatments. The example provided here, is one of the interesting observations arose from the ImmunoAgeing study. In addition, at 18 months after the beginning of the project, it finds itself in a data collection stage that will move through a data analysis stage during the next months.

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