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Is human immunosenescence clinically relevant?
Looking for 'immunological risk phenotypes'
  Trends in Immunology
Volume 23, Issue 7, 1 July 2002, Pages 330-332
Graham PawelecE-mail The Corresponding Author, a, Qin Ouyanga, Giuseppina Colonna-Romanob, Giuseppina Candoreb, Domenico Liob and Calogero Carusob
a Tubingen Ageing and Tumour Immunology Group, Center for Medical Research, Waldhornlestrasse 22, D-72072, Tubingen, Germany
b Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134, Palermo, Italy
from Jules: at CROI researchers presented the 1st study data that I know of finding in HIV that senescence is associated with a clinical outcome, in this case the study found the association with CVD.
The 3rd ImAginE Conference on 'Basic Biology and Clinical Impact of Immunosenescence' was held at Palermo University, Italy from 10-13 April 2002.
Establishment of 'immunological risk phenotypes' might help to predict and eventually influence remaining longevity in the very elderly, and, as discussed at this meeting, possibly also the not-so-elderly.
The meeting addressed the questions of establishing what immunosenescence is, what biomarkers for this state can be put forward, and what clinical impact ageing of the immune system has in humans.
Immunological risk phenotypes
Susceptibility and sensitivity to infectious disease increase in the elderly and the only continuously accelerating cause of death in the very elderly is likely to be infectious disease [1 and 2]. In Swedish biobehavioural longitudinal studies of the very elderly, it is the state of the immune system that is paramount in controlling remaining longevity and it is possible to identify 'immunological risk phenotypes' (IRP) predictive of remaining longevity [3]. Such IRP seem to be independent of the health status of the subjects at the beginning of the study (Nilsson, Jonkoping University, Sweden). This is an important point, given the known effect of health status on immunogerontological phenotypes [3 and 4]. Efforts to refine the IRP and increase its predictive powers, extending them to younger individuals, are crucial and ongoing.
The concept might also be applied to monitoring the results of interventions, for example predicting the response to vaccination in the elderly (Grubeck-Loebenstein, Innsbruck, Austria). It has been known for some time that seropositivity for cytomegalovirus (CMV) is associated with the IRP [5]. Moreover, it is emerging that the clonal expansions commonly seen in CD8 cells from middle age onwards might be because of an 'obsession' of the immune system with CMV [5]. MHC-peptide tetramers for various different CMV or Epstein-Barr virus (EBV) epitopes allow direct quantification of virus-specific cells and reveal clonal expansions in the elderly, predominantly for CMV rather than for EBV (Sansoni, Parma, Italy). When the elderly are divided into two groups based on their IRP, these extreme clonal expansions of CMV-specific CD8 cells are seen only in subjects belonging to the at-risk group. The majority of these cells are not functional, at least in terms of specific interferon-γ (IFN-γ) production, suggesting that much of the 'immunological space' might be taken up by dysfunctional T cells, and that this contributes to the IRP (Ouyang, Tubingen, Germany).
Further refinement of the immunological risk phenotype
Microarrays, although technically demanding, generate large amounts of data that have further implied age-associated changes in signal transduction, stress responses, metabolic status and surface molecule expression (Taub, Baltimore, MD, USA), which are certainly expected to contribute to improved biomarker definition. Proteomics approaches are also beginning to yield potential new biomarkers of ageing in T cells (Radziszewska, Bedford, UK). More information on lymphocyte kinetics is essential for understanding immunosenescence, and preliminary data obtained with the elegant technique of heavy-glucose labelling indicate that turnover of dividing cells of both CD4 and CD8 phenotype is more rapid in the young than in the elderly, with the possible exception of CD8+ CD45RA+ cells (Wallace, Compton, UK).
Measuring telomere lengths and maintenance thereof is also expected to contribute to defining better IRP (Mariani, Bologna, Italy; Pawelec, Tubingen, Germany). More sophisticated bioinformatics and mathematical modelling is also required and is in the process of being applied (Valensin, Bologna, Italy; Yashin, Rostock, Germany). It is anticipated that application of these and additional modern analytical techniques will enable rapid development and exploitation of more sophisticated and rigorous IRP.
What determines the immunological risk phenotype?
The factors responsible for determining individual susceptibility to the IRP are currently unknown and are the focus of intense current research. They will certainly be multifactorial, probably including interactions between genetic and environmental control of several parameters: cytokine levels (Ershler, Washington DC, USA; Rea, Belfast, UK; Hurme, Tampere, Finland; Caruso, Palermo, Italy; Paganelli, Chieti, Italy); hormone levels and hormone receptor function (Globerson, Beer-Sheva, Israel; Beckman, Perth, Australia); antioxidant defences and DNA repair (Barnett, Coleraine, UK; Doria, Rome, Italy; Frasca, Miami, FL, USA); proteasome function (Ponnappan, Little Rock, AR, USA); apoptosis control (McLeod, Bristol, UK; Gupta, Irvine, CA, USA; Fulop, Universite de Sherbrooke, Canada; Cossarizza, Modena, Italy); histone acetylation status (Sourlingas, Athens, Greece); levels of cell types, such as NK-T cells (Solana, Cordoba, Spain) or CD4+ CD25+ suppressor cells (Akbar, London, UK); and levels of positive and negative costimulatory molecules on T cells (Sikora, Warsaw, Poland; Pawelec, Tubingen, Germany).
Inflammation and the immunological risk phenotype
Many aspects of ageing involve inflammatory processes, and ageing is associated with chronic, low-grade inflammatory activity, leading to long-term tissue damage [6]. The IRP might be associated with the inability to control systemic inflammation as shown by the population-based study of healthy 81-year-old Danes, where low-grade elevations in systemic tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were associated with all-cause mortality, independently of each other and of other confounding factors (Bruunsgaard, Copenhagen, Denmark).
It now needs to be assessed how much these changes depend on the immunogenetic background and how much on the natural history of the individual (i.e. on extra burdens of antigenic load, such as chronic infections [7]). New data indicated that the IL-6 -174 C/G polymorphism involved in IL-6 high production is predictive of mortality in the elderly affected by acute myocardial infection or unstable angina (Franceschi, Bologna, Italy), and that there is a significant increase of the 'anti-inflammatory' (IL-10 -1082GG/TNF-α -308GG) genotype in centenarians compared with controls (Lio, Palermo, Italy). Therefore, possession of a genotype able to control inflammatory status might allow successful ageing and conversely proinflammatory genotypes might cause IRP.
Concluding remarks
Establishing better biomarkers of immune ageing and improved definition of IRP will allow more accurate monitoring of the results of interventions aimed at preventing or reversing age-associated immune dysfunction. Currently, the only type of intervention likely to have a significant effect remains caloric restriction (CR). Most published results are from mice [8], but studies on rhesus monkeys are reaching maturity, and among many different effects, the impact of CR on immune function can also be seen (Roth, Baltimore, MD, USA). In-vitro studies using antioxidants suggest a potential benefit (Hyland, Coleraine, UK), and telomerase transfection could immortalize T cells without triggering neoplastic changes (Dagarag, Los Angeles, CA, USA). Other manipulations still belong to the realm of fantasy and unscrupulous anti-ageing companies.
Key outcomes of the meeting
· Microarray techniques and proteomics approaches are beginning to yield potential new biomarkers of ageing.
· Measuring telomere lengths and maintenance thereof is expected to contribute to defining better immunological risk phenotypes.
· Extreme clonal expansions of CD8 cells related to antigenic load such as cytomegalovirus chronic infection are seen only in subjects belonging to the immunological risk phenotypes.
· Possession of a pro-inflammatory cytokine genotype could play a role in determining immunological risk phenotypes (conversely, possession of a cytokine genotype able to control inflammatory status might allow greater longevity).
We would like to apologize to all those speakers whose excellent work, owing to space limitations, could not be mentioned in this brief report. For more details, please see the forthcoming special issue of the journal 'Mechanisms of Ageing and Development'. This meeting was the third conference held under the auspices of the EU Thematic Network 'Immunology and Ageing in Europe, ImAginE', contract no. QLK6-CT-1999-02031 (
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