Morbidity does not influence the T-cell immune risk phenotype in the elderly: findings in the Swedish NONA Immune Study using sample selection protocols

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Abstract

A critical issue in our understanding of ageing and the immune system refers to the health status of the population from which inferences are drawn. The commonly used SENIEUR protocol, selecting individuals representing ‘normal ageing’ has recently been under debate because a substantial amount of individuals with various health problems are excluded. The aim of the present study was to investigate the influence of morbidity on immune parameters and to evaluate the associations with the T-cell immune risk phenotype (IRP), related to cytomegalovirus (CMV) seropositivity by applying the SENIEUR protocol and the OCTO-Immune protocol in the unselected population based sample (n=138) of oldest-olds, participating in the Swedish NONA Immune Study. The SENIEUR protocol excluded over 90% of the sample whereas the OCTO-Immune protocol excluded almost 65% of the sample. Three independent groups, very healthy (SENIEUR), moderately healthy (OCTO-Immune) and frail (non-SENIEUR/non-OCTO-Immune) were created. Flow cytometry studies on lymphocyte sub-populations revealed no significant difference in CD4/CD8 ratio, CD3+CD4−CD8+, CD3+CD4+CD8−, CD8+CD57+CD28−, CD8+CD56+CD57− or CD8+CD56+CD57+ between the very healthy, moderately healthy and the frail subsamples. Our findings indicate that morbidity does not significantly influence the T-cell immune risk profile in the elderly, and we suggest the inclusion of broader samples in future immunogerontological studies.

Introduction

Studies on the immune system in the elderly are often performed on highly selected samples by the use of protocols that exclude subjects with conditions that influence the immune system. The widely used SENIEUR protocol (Ligthart et al., 1984), based on a consensus from EURAGE concerted action program on ageing of the European community, and represents the most comprehensive set of criteria for sample selection. The SENIEUR protocol exclude individuals with certain compromised health characteristics and helps distinguishing between primary and secondary ageing, i.e. alterations caused by ageing per se and those associated with disease. Another selection protocol for healthy elderly is that proposed by Hallgren et al. (1988). This protocol excludes individuals, with diseases and other conditions known to affect the immune system, i.e. state exclusion criteria that are tailored to the particular study situation. However, in studying the elderly the excluded proportion is often substantial and increases with age due to increased morbidity. It was estimated that about 90% of seniors admitted to congregate housing were excluded when using the SENIEUR protocol. Consequently the value of this protocol has recently been under debate (Castle et al., 2001, Ershler, 2001, Ligthart, 2001, Miller, 2001, Pawelec et al., 2001).

To our knowledge there are few studies that examined the effects of sample selection criteria, defined by various protocols, on immune system parameters. We have previously reported an immune risk phenotype (IRP) of lymphocyte subsets in octogenarians that was associated with elevated 2-year mortality (Wikby et al., 1994, Wikby et al., 1998, Olsson et al., 2000). The IRP includes a combination of high CD8 and low CD4 proportion and poor T-cell proliferation in peripheral blood lymphocytes. In particular, these individuals have a very significant CD8 lymphocytosis associated with a major expansion of CD8+CD45RA+CD27−, CD8+CD57+CD28− and CD8+CD56+CD57+ T-cell subsets, representing highly overlapping populations. Recent data suggest that these markers are associated with cytomegalovirus (CMV) infections (Looney et al., 1999, Olsson et al., 2000, Wikby et al., 2002). An unresolved issue in this context is the association between these findings and morbidity in a broader sense.

In the present study we have applied a modified SENIEUR and a modified Hallgren (hereafter OCTO-Immune) selection protocol in a population-based sample of individuals aged 86, 90 and 94 to investigate the impact of various exclusion criteria on the exclusion rate using these protocols. The use of these criteria also permitted us to distinguish subgroups of very healthy, moderately healthy and frail individuals for comparison of various T-cell subsets. The T-cell subsets investigated include the CD3+CD8+CD4−, CD3+CD8−CD4+ and the CD8+CD57+CD28−, CD8+CD45RA+CD27−, CD8+CD56+CD57+ T-cell subsets as well as the CD4/CD8 ratio previously found to be associated with an IRP (Wikby et al., 2002).

Section snippets

Subjects

The sample for the NONA Immune study was recruited among participants in the NONA Study, in which a population-based sample of oldest-old individuals are investigated (Wikby et al., 2002). Blood for the immunological analyses were drawn in 138 individuals. All subjects were examined in their place of residence. The blood samples were drawn in the morning between 0900 and 1000 h. The mean age of the sample was 90 years with a total proportion of women of 70% (Table 1). While 60.9% lived in

Step by step exclusion of individuals using different protocols

The study population initially consisted of 138 individuals. The exclusion criterion that reduced the sample at most was applied first. This principle was then used in subsequent steps. By applying the modified SENIEUR protocol (Table 2), only 13 individuals (9.4%) remained after the final exclusion. Table 3 shows that 51% (71/138) of the sample was excluded by the most common exclusion criterion, cardiac insufficiency. Medication with known influence on the immune system was the second most

Discussion

The present study examined the effects on a selected set of immune parameters of two different sample selection protocols proposed for studies on ageing and immunology. We used a population-based sample of oldest-old individuals to examine the effects of a step by step exclusion. In accordance with previous information (Castle et al., 2001), we found that the SENIEUR protocol excluded a large portion, 90%, of the sample. The original protocol, suggesting additional laboratory analyses for

Acknowledgements

We thank the nursing staff, including Lena Svensson, Lena Blom, and Monica Janeblad for invaluable help with collection of the blood samples, and Andrea Tompa for administrative and technical assistance. The study was supported by grants from the Research Board in the County Council of Jönköping, and the scientific council at Ryhov hospital. The NONA Immune Study is part of the Thematic Network ‘Immunology and Ageing in Europe’ (ImAginE).

References (30)

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    Citation Excerpt :

    The OCTO study focussed on individuals born around 1900 who were selected for good health and therefore excluded the majority of 85-year-olds, but the later NONA study examined a representative population of (free-living) individuals, only one-third of whom would have been included in OCTO. The results of these studies led to the concept of an “immune risk profile” (Pawelec et al., 2001) which was in fact quite similar in both OCTO and NONA (Nilsson et al., 2003). However, this IRP was quite weakly associated with 2-, 4- and 6-year mortality; a pro-inflammatory serostatus and cognitive impairment was more predictive of mortality, but the presence of both risk factor clusters in the same person was much more strongly associated with incipient mortality (Wikby et al., 2005).

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