An integrated approach to dissect determinants, risk
factors and pathways of ageing of the immune system
Few studies have assessed the impact of genetic variation on the quantitative regulation of levels of the human cellular and humoral arms of the immune system. Likewise, there is limited information about differences of the observed phenotypic and genetic variability acting through time during ageing. Knowing the genetic variants affecting the circulating levels of cell types and molecules showing major changes during ageing should allow the assessment of the impact of inherited variation on key immunological and clinical features of immunosenescence.
The role of specific environmental exposures in promoting the changes and clinical features of immunosenescence remains comparably uncertain. For instance, it is unclear how much quantifiable modifiable factors such as smoking, diet, alcohol intake and physical activity influence the ageing of the immune system.
A particularly notable feature of immunosenescence recognized, but measured only grossly is the substantial contraction of the immune repertoire (of both B and T cells), apparent as a progressive diminution of the naïve and expansion of the memory compartments, and thought to result from selection driven by environmental triggers. This highlights the importance of environmental influences on the initiation and progression of immune dysfunction as we age, with the increasing antigen experience of ageing individuals among the principal drivers of repertoire contraction and, potentially, dysfunction. For example, most influenza-specific B cell responses in the elderly are derived from modifications of pre-existing populations rather than the generation of de novo responses from naïve precursors. Analyses to date have been limited in resolution, because they have generally been conducted on small cohorts.
The paradoxical concurrent presence in the elderly of signs of immune deficiency (increased susceptibility to infection, reduced responses to vaccination) and inappropriate immune responses (increased inflammation and tendency toward autoimmunity) is especially puzzling. From an evolutionary perspective, genetic risk factors promoting autoimmune disease persist within a population due to a previous or concurrent protective effect from prevalent infections. The ‘broken’ relationship during immunosenescence suggests that distinct pathways and mechanisms may also contribute to the immune dysfunction with autoreactivity in the elderly. Furthermore, apart from overt autoimmune disease, increasing autoreactivity during ageing is also indicated by the increased prevalence of detectable serum autoantibodies in healthy elderly cohorts, reaching >50% for certain specificities in comparison with <2% in younger populations although again, the breadth of this response has not been characterised. The development of such age-related autoreactivity is thought to be a complex result of combined inherited factors (as indicated by their increased levels in first degree relatives of autoimmune patients and largely unknown environmental and stochastic factors.
Overall, studies on immunosenescence have been very fragmentary with limited possibility to connect the various pieces of evidence. For instance, it is possible that the chance of generating and expanding auto-reactive clones will increase over time, through somatic hypermutations and cross-reactivity of the BCRs in B cell populations skewed by chronic exposures to viruses and other microbes, thus providing an explanation for the contemporaneous presence of immunodeficiency and auto-reactivity.
In general, the limited a priori knowledge about the changes of the immune system in ageing humans and about key variables such as underlying genetic controls hampers functional studies to examine specific biological features and mechanisms of immunosenescence. In turn, the lacuna in characterizing the changes of the immune system in ageing humans and understanding the underlying mechanisms prevents the elucidation of the pathways actually contributing to immunosenescence and hinders the design of therapies and preventive medical programs. This has a major impact on public health, especially as the demography of populations shifts toward increased age worldwide.
The ImmuneoAgeing project is an integrated approach, built on complementary genomic, transcriptomic, and functional testing bioresources and expertise of the participating partners, to characterize immunoageing and analyse its genetic and epidemiological determinants in detail, thereby overcoming current limitations in knowledge.