Immune Risk Phenotype Research Articles

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels.

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population.

Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians [GO]) and premature (Down syndrome [DS]) immunosenescence. The TTV load was positively associated with age, cytomegalovirus (CMV) antibody levels, and the Cu/Zn ratio and negatively associated with platelets, total cholesterol, and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (Randomly Recruited Age-Stratified Individuals From The General Population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with ≥4log TTV copies/mL had a higher risk of having a CD4/CD8 ratio<1 than those with lower viremia (odds ratio [OR] = 2.85, 95% confidence interval [CI]: 1.06-7.62), as well as reduced CD3+ and CD4+T-cells compared to males with lower replication rates (<4log), even after adjusting for CMV infection. In summary, differences in immune system preservation are reflected in the models of delayed and premature immunosenescence, displaying the best and worst control over TTV replication, respectively. In the general population, TTV loads were negatively associated with CD4+ cell counts, with an increased predisposition for an inverted CD4/CD8 ratio for individuals with TTV loads ≥4log copies/mL, thus promoting an immune risk phenotype.

Better satisfaction with life is associated with normal immune profile (CD4/CD8 ratio) – and dependent on the successful aging status – in older Brazilian individuals

Introduction: The immune system is an important determinant of longevity and has also contributed to the way individuals feel as they reach older ages. The inverted CD4/CD8 ratio is a parameter of the immune risk phenotype, and its prevalence increases with age. Association between immunological function, cognition and mood has been supported by studies with clinical and aging populations. Objective: We explored the relationship between the CD4/CD8 ratio and life satisfaction in a small sample of elderly people from Southern Brazil with good general health. Method: The sample consisted of 44 elderly individuals, who participated in an aging study in Southern Brazil (the PALA Study), and accepted to continue in the investigation collecting additional blood sample for the CD4/CD8 analysis. From this sample, 52% (N = 23) presented successful aging according to Rowe and Kahn’s criteria. No participant was HIV positive or presented any autoimmune diseases. A questionnaire was applied for sociodemographic and clinical data, lifestyle, and occupational activity. Cognitive function, basic and instrumental activities of daily living, and depressive symptoms were evaluated with specific instruments. Life satisfaction was evaluated with the Life Satisfaction Scale from Diener et al. (1985). Results: Forty-two individuals (95%) showed CD4/CD8 ratio>1. CD4/CD8 ratio correlated significantly with life satisfaction (rho = -0.35) and with age (rho = -0.42) for the whole sample and among the successful aging sub-group only. Conclusion: This is an exploratory analysis with a small sample of elderly participants from a cohort started in 1996 in Southern Brazil (the PALA study). Their level of satisfaction with life was high, and correlated significantly, and inversely, with the CD4/CD8 ratio. It was also dependent on the successful aging status.

Objectively Measured Social Integration Is Associated With an Immune Risk Phenotype Following Marital Separation

Close relationships play an integral role in human development, and robust evidence links marital separation and divorce to poor health outcomes. Social integration may play a key role in this association. In many ways, the study of marital separation and divorce provides an ideal model system for a more complete understanding of the association between life stress and physical health. The current study investigated associations among objectively measured social integration, psychological distress, and biomarkers of immune health in recently separated adults (N = 49). We collected four measures of immune functioning-interleukin-6, C-reactive protein, and antibody titers to latent cytomegalovirus and Epstein-Barr virus-that were combined to yield a viral-Immune Risk Profile. To assess how variability in social integration is associated with immunological correlates following the end of a marriage, we incorporated observational ecological momentary assessment data using a novel methodology (the Electronically Activated Recorder). We found that objectively measured social behaviors are associated with concurrent viral-Immune Risk Profile scores over and above the effects of psychological distress and that psychological distress may be linked to biomarkers of immune health through social integration. This research expands current knowledge of biomarkers of immune health after divorce and separation and includes a new methodology for objective measures of social engagement.

Impact of illicit opioid use on T cell subsets among HIV-infected adults.

ObjectivesOpioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied.MethodsTo assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models.ResultsAmong 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05).ConclusionsAmong ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use.

Pre-transplant end-stage renal disease-related immune risk profile in kidney transplant recipients predicts post-transplant infections.

End-stage renal disease (ESRD) is associated with premature aging of the T-cell system. Nevertheless, the clinical significance of pre-transplant ESRD-related immune senescence is unknown. We studied whether immune risk phenotype (IRP), a typical feature of immune senescence, may affect post-transplant infectious complications. A total of 486 patients were prospectively studied during the first year post transplant. IRP was defined as positive cytomegalovirus serology with at least 1 of the following criteria: CD4/CD8 ratio <1 and/or CD8 T-cell count >90th percentile. We found that 47 patients (9.7%) had pre-transplant IRP. IRP+ patients did not differ from IRP- patients for any clinical characteristics, but exhibited more pronounced immune senescence. Both opportunistic infections (43% vs. 6%, P < 0.001) and severe bacterial infection (SBI) (40% vs. 25%, P = 0.028) were more frequent in IRP(+) patients. In multivariate analysis, IRP was predictive of both opportunistic infection (hazard ratio [HR] 2.97 [95% confidence interval {CI} 1.53-5.76], P = 0.001), and SBI (HR 2.33 [95% CI 1.34-3.92], P = 0.008). Acute rejection rates were numerically much lower in IRP+ patients. A total of 418 patients (86%) had biological evaluation 1 year post transplant. Among 41 IRP+ patients, 35 (85%) remained IRP+ 1 year post transplant. Pre-transplant IRP is associated with an increased risk of post-transplant infection.

Comprehensive Evaluation of the Immune Risk Phenotype in Successfully Treated HIV-Infected Individuals

BackgroundDespite successful treatment and CD4+ T-cell recovery, HIV-infected individuals often experience a profound immune dysregulation characterized by a persistently low CD4:CD8 T-cell ratio. This residual immune dysregulation is reminiscent of the Immune Risk Phenotype (IRP) previously associated with morbidity and mortality in the uninfected elderly (>85 years). The IRP consists of laboratory markers that include: a low CD4:CD8 T-cell ratio, an expansion of CD8+CD28- T-cells and cytomegalovirus (CMV) seropositivity. Despite the significant overlap in immunological phenotypes between normal aging and HIV infection, the IRP has never been evaluated in HIV-infected individuals. In this pilot study we characterized immune changes associated with the IRP in a sample of successfully treated HIV-infected subjects.Methods18 virologically suppressed HIV-infected subjects were categorized into 2 groups based on their IRP status; HIV+IRP+, (n = 8) and HIV+IRP-, (n = 10) and compared to 15 age-matched HIV uninfected IRP negative controls. All individuals were assessed for functional and phenotypic immune characteristics including: pro-inflammatory cytokine production, antigen-specific proliferation capacity, replicative senescence, T-cell differentiation and lymphocyte telomere length.ResultsCompared to HIV-infected subjects without an IRP, HIV+IRP+ subjects exhibited a higher frequency of TNF-α-producing CD8+ T-cells (p = 0.05) and a reduced proportion of CD8+ naïve T-cells (p = 0.007). The IRP status was also associated with a marked up-regulation of the replicative senescence markers CD57 and KLGR1, on the surface of CD8+T-cells (p = 0.004). Finally, HIV+IRP+ individuals had a significantly shorter mean lymphocyte telomere length than their non-IRP counterparts (p = 0.03).ConclusionsOur findings suggest that, despite similar levels of treatment-mediated viral suppression, the phenotypic and functional immune characteristics of HIV+IRP+ individuals are distinct from those observed in non-IRP individuals. The IRP appears to identify a subset of treated HIV-infected individuals with a higher degree of immune senescence.

Immunosenescence and aging in HIV.

During this era of unprecedented antiretroviral therapeutic efficacy, there is hope for successfully treated individuals to achieve a longevity approaching that of the general population. However, the recent identification of a higher incidence of cardiovascular, bone, metabolic, neurocognitive and other aging comorbidities is of major concern and may compromise that ability. The purpose of this review is to focus on the dynamic process of immune remodelling, known as immune senescence, which occurs during HIV infection, and how it impacts on long-term comorbidities. Early aging in those with HIV appears to stem from persistent chronic inflammation and residual immune activation despite successful antiretroviral therapy. Multiple similarities exist between the T-cell-senescent phenotypes found in many chronic autoimmune and inflammatory conditions, including HIV disease, and the elderly. The immune risk phenotype is linked to poor clinical outcomes in the elderly and may also have clinical consequences in those with HIV. Immune senescence results in functional impairments of immunity and a reduced ability to adapt to metabolic stress. Understanding the factors driving the development of immune senescence is critical for the development of strategies to prevent early aging.

Inverted CD4:CD8 ratio is not associated with three-year mortality in a sample of community-dwelling oldest old: the OCTABAIX immune study.

The presence of an immune risk phenotype (IRP) has been correlated with survival rates in elderly people. To determine whether an inverted CD4:CD8 ratio might be a marker of IRP in a sample of oldest old by assessing its relationship with mortality. Prospective cohort study. Community-based survey study of seven primary healthcare centres. 328 people born in 1924 and registered with primary healthcare centres. Chronic drug prescription, functional status (Barthel and Lawton indexes) and cognitive status (Spanish version of the Mini-Mental State Examination) were recorded. CD4:CD8 ratios were determined, with a ratio of 1.00 or less being used to define IRP. The CD4:CD8 ratio was 1.00 or less in 47 subjects (15.6%). After three years, 51 subjects had died (16.3%); 9 were from among the 47 (19.1%) with an inverted CD4:CD8 ratio and 42 (15.8%) from the remainder (P=0.52). Multivariate analysis identified two significant clinical variables (Lawton Index scores and the number of chronic drugs prescribed) as being independent predictors of three-year mortality risk in this cohort of octogenarians. This risk profile did not change when introducing the CD4:CD8 ratio into the calculation. In this community-dwelling population of oldest old (85 years old at baseline) an inverted CD4:CD8 ratio was not associated with three-year mortality.

Chronic Viral Infections and Immunosenescence, with a Focus on CMV

The term immunosenescence is used to describe the decreased function of the system with age, and al- so to describe the phenotypic alterations in cells and cytokines that develop with age. The most dramatic pheno- typic change is seen in the T cell compartment, where the percentage of cells with an effector memory increas- es, and the number and diversity of naive cells decrease. In particular, large, often oligoclonal accumulations of CD28- CD8+ T cells develop. This hallmark change is largely attributable to CMV infection; the accumulating cells are the enormous inflationary virus-specific T cell population that are responding to this lifelong, smouldering, subclinical in- fection. In many populations, at least 80% of the elderly carry CMV, so CMV-driven changes in old age were easily as- cribed to aging per se. There is broad agreement that CMV drives this characteristic of the aged sys- tem. There is also considerable evidence that the size of the CD8+CD28- population can be used to describe an immune risk phenotype which correlates with an increased inflammatory milieu (inflammaging), which may be a predictor of all cause mortality. However, the evidence that CMV contributes causally to the functional failings of the system in old age, rather than innocently providing a convenient biomarker, is much less convincing. This important question needs to be addressed with studies including enough CMV seronegative individuals to provide statistically valid data.

Immune risk phenotype is associated with nosocomial lung infections in elderly in-patients

BackgroundNosocomial infections are extremely common in the elderly and may be related to ageing of the immune system. The Immune Risk Phenotype (IRP), which predicts shorter survival in elderly patients, has not been evaluated as a possible risk factor for nosocomial infection. Our aim was to assess the prevalence of nosocomial infections in elderly in-patients and to investigate potential relationships between nosocomial infections and the immunophenotype, including IRP parameters.ResultsWe included 252 consecutive in-patients aged 70 years or over (mean age, 85 ± 6.2 years), between 2006 and 2008. Among them, 97 experienced nosocomial infections, yielding a prevalence rate of 38.5% (95% confidence interval, 32.5-44.5). The main infection sites were the respiratory tract (21%) and urinary tract (17.1%) When we compared immunological parameters including cell counts determined by flow cytometry in the groups with and without nosocomial infections, we found that the group with nosocomial infections had significantly lower values for the CD4/CD8 ratio and naive CD8 and CD4 T-cell counts and higher counts of memory CD8 T-cells with a significant increase in CD28-negative CD8-T cells. Neither cytomegalovirus status (positive in 193/246 patients) nor presence of the IRP was associated with nosocomial infections. However, nosocomial pneumonia was significantly more common among IRP-positive patients than IRP-negative patients (17/60 versus 28/180; p = 0.036).ConclusionImmunological parameters that are easy to determine in everyday practice and known to be associated with immune system ageing and shorter survival in the elderly are also associated with an elevated risk of nosocomial pneumonia in the relatively short term.

Differences according to gender and health status in CD4:CD8 ratio in a sample of community-dwelling oldest old. The OCTABAIX immune study

The presence of an immune-risk phenotype (IRP) has been correlated with survival rates in elderly people. The aim of this study is to characterize the inverted CD4:CD8 ratio as a possible marker of IRP in a sample of oldest old (85 years) by assessing differences in gender and health status. Comorbidity, functional status (Barthel Index), and cognitive status with the Spanish version of the Mini-Mental State Examination were evaluated. Non-disabled subjects were defined as those with better health status, with scores of >90 on the Barthel Index and >23 points on the Spanish version of the Mini-Mental State Examination. CD4:CD8 ratios were recorded, and a ratio of 1.00 or less was used to define IRF. Three hundred and twelve subjects aged 85 years old were studied, 190 women (60.9%) and 122 men. The CD4:CD8 ratio was 1.00 or less in 47 subjects (15.6%) and higher than 2.2 in 115 (36.8%). There were no differences in CD4:CD8 ratio according to health status. The inverted CD4:CD8 ratio was more frequent in men (55.3%). In this community-dwelling, single year birth cohort study, the subgroup with poor health status did not have a lower CD4:CD8 ratio. The inverted CD4:CD8 ratio was more frequent in men.

An aged T cell phenotype: A prognostic indicator in liver transplant recipients?

There is now little doubt that aging has a profound effect on both the innate and adaptive arms of the immune system that results in a decline in immunity termed immunosenescence. This is evidenced by increased susceptibility to bacterial and viral infections, reactivation of latent infections (herpes zoster leading to shingles), increased production of autoantibodies, and decreased response to vaccination in older adults. Two key drivers for senescence in the adaptive immune system are thymic involution, which reduces the output of naive T cells, and consequent homeostatic expansion of the peripheral T cell pool. Moreover, with repeated antigen exposure and proliferation of memory T cells throughout life, there is also shortening of telomeres, which limits the proliferative capacity of T cells and eventually results in replicative senescence. With repeated stimulation, T cells also become highly differentiated: they lose costimulatory receptors such as CD28, CD27, cytotoxic T lymphocyte antigen 4, and inducible T cell costimulator, up-regulate inhibitory receptors such as killer cell lectin-like receptor subfamily G member 1, and acquire expression of immune effector molecules, including killer cell immunoglobulin-like receptors, chemokines, and chemokine receptors. Each of these factors contributes to the agerelated loss of T cell responsiveness and can be considered a biomarker for the biological age of an individual’s immune system. Importantly, longitudinal studies have revealed that T cell immunosenescence is associated with increased morbidity and mortality, and specific age-related changes in the T cell phenotype have been proposed to represent an immune risk phenotype. Shortened leukocyte telomeres are associated with several agerelated pathologies, including cardiovascular disease and cancer, and the number of CD4þCD28 T cells is increased in patients with autoimmune inflammatory diseases such as rheumatoid arthritis. In this issue of Liver Transplantation, Gelson et al. report on their investigation of whether the chronic immune stress of organ transplantation accelerates aging of the immune system. It has already been well documented in the literature that transplant recipients have an increased incidence of cancer, cardiovascular disease, and infections, but this has been largely ascribed to the effects of the long-term use of immunosuppressants. However, the authors show clearly that another possible factor contributing to excess morbidity and mortality in established organ graft recipients is senescence of the immune system as liver graft recipients had shorter T cell telomeres and more cells of a mature phenotype than healthy age-matched controls. Interestingly, multiple linear regression analyses of case and control data have allowed Gelson et al. to estimate the impact of organ grafts and comorbidities on T cell telomere length, and this has allowed them to gauge the effect in terms of relative T cell aging. Thus, those patients with established liver grafts had 1 year added to their T cells’ biological clock, whereas patients with hepatocellular carcinoma at transplantation or skin malignancy subsequent to transplantation had 6.2 and 3.7 additional years, respectively. Crucially, the use of immunosuppressive drugs was not independently associated with shortened telomeres or an increase in cells with a mature

Evidence of premature immune aging in patients thymectomized during early childhood

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

Psychologically adverse work conditions are associated with CD8+ T cell differentiation indicative of immunesenescence

Numerous studies have demonstrated associations between psychosocial stress and indices of poor health, and much research is now dedicated to identifying the responsible biological mechanisms. The current study examined the hypothesis that stress may impact health by promoting immunesenescence. Participants were 537 factory workers (89% male; mean age 44; range 18–65 years). Blood was analyzed for two components of the aging ‘immune risk phenotype’: the number and proportion of late-differentiated (CD27−CD28−) CD8 T cells (CTLs) and CD4:CD8 ratio. Psychological assessment focussed on work-related stressors which have previously been found to predict morbidity and mortality. This assessment included measures of work load, effort–reward imbalance, and social support at work. High levels of job stress (low reward, high effort–reward imbalance) and low social support at work were associated with a significantly lower CD4:CD8 ratio. Also, the number of CD27−CD28− CTLs was 30% to 50% higher in employees classified in the highest tertile of each stress parameter as compared to employees in the corresponding lowest tertile ( p < .01). These associations withstood adjustment for a wide range of demographic, life style, medical, and socio-economic indicators. The associations between CTL phenotype and low social support became stronger with increasing age. These results suggest that psychosocial stress may contribute to immunological aging. Prospective studies should address the long-term consequences of these associations for healthy aging.

High serum YKL-40 level in a cohort of octogenarians is associated with increased risk of all-cause mortality

YKL-40 is secreted by macrophages, neutrophils, chondrocytes, endothelial-, vascular smooth muscle- and cancer cells. Interleukin (IL)-6 stimulates YKL-40 production in human in vivo studies. High serum YKL-40 is associated with poor prognosis in patients with inflammatory diseases and cancer. We studied whether serum YKL-40 was associated with systemic low-level inflammation, an immune risk phenotype, and mortality in relatively healthy 80-year old humans. Serum YKL-40, IL-6 and tumour necrosis factor (TNF)-alpha were measured by enzyme-linked immunosorbent assays (ELISAs) in octogenarians (n = 151) and serum YKL-40 in 18-30-year-olds (n = 89). Fifty-one of the octogenarians died during the 6-year follow-up. Serum YKL-40 in octogenarians was higher compared to the level in young people (median 116 versus 31 microg/l, P < 0.0005). Serum YKL-40 correlated with serum IL-6 in elderly women (Spearman's rho = 0.30, P = 0.009) and men (rho = 0.25, P = 0.003), but only with serum TNF-alpha (rho = 0.23, P = 0.05) and C-reactive protein (CRP) (rho = 0.57, P < 0.0005) among the elderly women. In addition, high serum level of YKL-40 was associated with a low CD4 : CD8 cell ratio. Univariate analysis of serum YKL-40 (logarithmically transformed and divided by tertiles) showed significant association with all-cause mortality [tertile 3: hazard ratio (HR) = 2.38, 95% confidence interval (CI): 1.19-4.78, P = 0.02]. The effect persisted after adjusting for potential confounders (sex, smoking, body mass index, chronic disease and anti-inflammatory medicine). These results suggest that serum YKL-40 is a prognostic and sensitive biomarker of all-cause mortality in octogenarians.

Autoantikörper – physiologisches Phänomen oder Ausdruck von Krankheit?

The prevalence of autoantibodies in otherwise healthy individuals increases with age. This phenomenon has been described for a number of different autoantibodies and is not gender-specific. The cause of autoantibody production in the elderly is likely to be the consequence of a dysregulation of the immune system developing in the context of aging (immunosenescence). Autoantibodies alone seem not to be able to cause autoimmune disease without additional triggers. However, their increased prevalence in the elderly might create an immune-risk phenotype.

Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

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

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.

Longitudinal Studies of Clonally Expanded CD8 T Cells Reveal a Repertoire Shrinkage Predicting Mortality and an Increased Number of Dysfunctional Cytomegalovirus-Specific T Cells in the Very Elderly

The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.