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The immune risk phenotype is associated with IL-6 in the terminal decline stage: Findings from the Swedish NONA immune longitudinal study of very late life functioning
Department of Natural Science and Biomedicine, School of Health Sciences, Jo¨nko¨ping University, Box 1026, 551 11 Jönköping, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
Unilever Corporate Research, Colworth House, Sharnbrook MK44 ILQ, UK.
Unilever Corporate Research, Colworth House, Sharnbrook MK44 ILQ, UK.
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2006 (English)In: Mechanisms of Ageing and Development, ISSN 0047-6374, E-ISSN 1872-6216, Vol. 127, no 8, 695-704 p.Article in journal (Refereed) Published
Abstract [en]

In the present NONA immune longitudinal study, we further examine the previously identified T cell immune risk phenotype (IRP), relative inflammatory activity, morbidity and 2-year mortality in very old individuals >90 years. T-cell subsets as well as the inflammatory markers IL-6, IL-10, C-reactive protein, transthyretin and albumin were evaluated. IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells. The further characterisation of these exceptional individuals may allow insight into remedial approaches for those who remain in the IRP category until death. © 2006 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier , 2006. Vol. 127, no 8, 695-704 p.
Keyword [en]
Immune risk; T-cells; Inflammation; Interleukin 6; Survival
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-37496DOI: 10.1016/j.mad.2006.04.003Local ID: 36405OAI: diva2:258345
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-04-07
In thesis
1. The Immune System in the Oldest-Old: Clinical and Immunological Studies in the NONA Immune Cohort
Open this publication in new window or tab >>The Immune System in the Oldest-Old: Clinical and Immunological Studies in the NONA Immune Cohort
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The oldest-old (people aged 80 or older) constituted 5 % of the population in Sweden in 2000, an increase from 1.5 % fifty years earlier. The immune system undergoes dramatic changes at high age, sometimes referred to as “immunosenescence”. However, the natures of these changes, and in particular, their clinical consequences are incompletely understood. In a previous longitudinal study, a set of immune parameters were identified and termed immune risk phenotype (IRP) because of an association with increased mortality. The IRP consists of changes in the T lymphocyte compartment, in particular an inverted CD4/CD8 ratio. The IRP was found to be associated with cytomegalovirus (CMV) infection, which through expansions of cytolytic anti-viral CD8 cell responses was ascribed a role in the development of IRP. The general aim of this thesis was to increase the knowledge of changes in the immune system and their clinical consequences in the oldest-old. The population-based random sample of the longitudinal NONA-Immune Study (n = 138, mean age 90 years at baseline) was used for all investigations.

In paper I, the effects on sample size of various exclusion protocols for immune studies of the elderly was examined. The commonly used SENIEUR protocol, selecting individuals representing ‘normal ageing’, excluded 90 % of nonagenarians. Based on different protocol criteria, individuals were grouped into ‘very healthy’, ‘moderately healthy’ or ‘frail’. The prevalence of CMV was similar across the groups. Further, differentiated CD8 populations associated with CMV, i.e. those expressing CD56, CD57 and CD45RA while lacking expression of CD27 and CD28, were equally distributed across the groups of the oldest-old, but were, as expected, significantly increased in the elderly compared to a middle aged control group. The findings showed that lymphocyte subsets associated with IRP might serve as significant biomarkers of ageing independent of the overall health status, also supporting the notion that immunological studies of the oldest-old should be done in population-based non-selected populations.

The IRP and the presence of low-grade inflammation, for example increase of   IL-6 in plasma, constitute major predictors of 2-year mortality in the oldest-old. In paper II, the CD4/CD8 ratio and IL-6 were found to predict 97 % of observed survival and 57 % of deaths over 2 years. The impact of IRP and IL-6 on 2-year survival was independent of age, sex and several diseases. The longitudinal design allowed temporal evaluations, suggesting a sequence of events starting with IRP and leading to inflammation in the decline state.                                      Four-year mortality in the oldest-old (paper III) was found to be mainly related to markers of inflammation and IRP. Individuals with both inverted CD4/CD8 ratio and high IL-6 level had significantly higher 4 year mortality (82 %) compared to individuals with CD4/CD8 ratio ³ 1 and low IL-6 level (29 %) at baseline. The presence of IRP and increased IL-6 level showed some associations with presence of diseases; in particular, IL6 was associated with the presence of cognitive impairment. However, despite being strong predictors of mortality, IRP and IL-6 could not be linked to any specific cause of death, probably due to the multi-factorial nature of these factors.                                                                                                                             The prevalence of antinuclear antibodies (ANA) in the oldest-old was higher compared to younger controls (paper IV). The difference across age was most pronounced in men, showing low levels at younger age, whereas the prevalence among the oldest-old men reached a similar level as in women. There was no association between the presence of ANA and IRP, CMV status or health status in the oldest-old.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 75 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1172
Elderly, selection, health status, lymphocyte subsets, CD8, CMV, cytomegalovirus, immune risk, immune risk phenotype, IRP, T-cells, interleukin 6, IL-6, survival, mortality, antinuclear antibodies, ANA, ageing, immunosenescence
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-54672 (URN)978-91-7393-429-9 (ISBN)
Public defence
2010-04-23, Originalet, Qulturum, Hus B4, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
Available from: 2010-04-07 Created: 2010-03-31 Last updated: 2011-02-23Bibliographically approved

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Nilsson, Bengt-OlofErnerudh, Jan
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Infectious Diseases Faculty of Health SciencesClinical ImmunologyDepartment of Clinical Immunology and Transfusion Medicine
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