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The Immune System in the Oldest-Old: Clinical and Immunological Studies in the NONA Immune Cohort
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1172
Keyword [en]
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
Identifiers
URN: urn:nbn:se:liu:diva-54672ISBN: 978-91-7393-429-9 (print)OAI: oai:DiVA.org:liu-54672DiVA: diva2:306836
Public defence
2010-04-23, Originalet, Qulturum, Hus B4, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-04-07 Created: 2010-03-31 Last updated: 2011-02-23Bibliographically approved
List of papers
1. Morbidity does not influence the T-cell immune risk phenotype in the elderly: Findings in the Swedish NONA Immune Study using sample selection protocols
Open this publication in new window or tab >>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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2003 (English)In: Mechanisms of Ageing and Development, ISSN 0047-6374, E-ISSN 1872-6216, Vol. 124, no 4, 469-476 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elesvier, 2003
Keyword
Elderly, Selection, Health status, Lymphocyte subsets, CD8, CMV
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26438 (URN)10.1016/S0047-6374(03)00024-1 (DOI)10981 (Local ID)10981 (Archive number)10981 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2010-04-07
2. 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
Open this publication in new window or tab >>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
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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
Keyword
Immune risk; T-cells; Inflammation; Interleukin 6; Survival
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37496 (URN)10.1016/j.mad.2006.04.003 (DOI)36405 (Local ID)36405 (Archive number)36405 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-04-07
3. The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal Study
Open this publication in new window or tab >>The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal Study
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In this NONA immune longitudinal study, we examine 4-year mortality in relation to a set of laboratory parameters, morbidity and cause of death in a population-based sample of oldest-old individuals (n=138). Four groups were constructed based on levels for the CD4/CD8 ratio (above or below one = IRP, immune risk phenotype group) and levels for IL-6 (below or above the median 3.15 pg/mL). 4-year mortality was higher in the “IRP” group (73 %), the “IL-6” group (64 %), and the “Double risk group” (82 %) compared with the “No risk” group (29 %; p-values between .005 and .000). Cognitive dysfunction and dementia were more common in the two groups with elevated IL-6 levels (p-values between .014 and .001), whereas cardiovascular disease tended (p = .081) to be associated with both “IRP” and “IL-6” groups. The most common cause of death was related to cardio- and cerebrovascular disease (59 %,), followed by infection in 15 % of the cases and cancer in 7 %. Despite their strong associations with 4-year mortality, neither IRP nor IL-6 could be linked to any specific cause of death, possibly because both IRP and IL-6 are multi-factorial risk factors, being associated with several different diseases and mechanisms which cause death.

Keyword
survival, mortality, CMV, cytomegalovirus, CD8, T-cells, inflammation, immuner risk phenotype, IRP, cause of death
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-54674 (URN)
Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2010-04-07
4. Antinuclear antibodies in the oldest-old women and men
Open this publication in new window or tab >>Antinuclear antibodies in the oldest-old women and men
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2006 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, no 4, 281-288 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to compare the prevalence of antinuclear antibodies (ANA) in very old individuals (≥86 years of age) with healthy younger (18-68 years) blood donors (n = 200) regarding gender, health status, ratio of circulating CD4/CD8 cells and cytomegalovirus (CMV) serology. Frozen plasma was used for ANA detection in two study groups, i.e. 'OCTO' (97 persons aged 86-92 years, 65% women) and 'NONA' (136 persons aged 86-95 years, 70% women). OCTO participants were recruited on the basis that they were healthy or moderately healthy according to a selection protocol. No exclusion criteria regarding health status were applied in the NONA sample. The prevalence of ANA was significantly higher in the oldest-old samples compared to blood donors. There was no association between health status and the presence of ANA in the oldest-old. The difference across age was most pronounced in men, with low levels at younger age, whereas the prevalence among the oldest-old men reached similar levels as in women. There were no associations between the presence of ANA and CD4/CD8 ratio or with CMV status in the oldest-old. Our findings confirm an increased prevalence of ANA in the oldest-old, and emphasize the importance of taking gender and age into consideration when evaluating ANA. © 2006 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2006
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37559 (URN)10.1016/j.jaut.2006.10.002 (DOI)36598 (Local ID)36598 (Archive number)36598 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2015-08-31

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