Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson's disease and cognition.

Alpha-synuclein pathology is associated with immune activation and neurodegeneration in Parkinson's disease. The immune activation involves not only microglia but also peripheral immune cells, such as mononuclear phagocytes found in blood and infiltrated in the brain. Understanding peripheral immune involvement is essential for developing immunomodulatory treatment. Therefore, we aimed to study circulating mononuclear phagocytes in early- and late-stage Parkinson's disease, defined by disease duration of less or more than five years, respectively, and analyze their association with clinical phenotypes. We performed a cross-sectional multi-color flow cytometry study on 78 sex-balanced individuals with sporadic Parkinson's disease, 28 controls, and longitudinal samples from seven patients and one control. Cell frequencies and surface marker expressions on natural killer cells, monocyte subtypes, and dendritic cells were compared between groups and correlated with standardized clinical scores. We found elevated frequencies and surface levels of migration- (CCR2, CD11b) and phagocytic- (CD163) markers, particularly on classical and intermediate monocytes in early Parkinson's disease. HLA-DR expression was increased in advanced stages of the disease, whereas TLR4 expression was decreased in women with Parkinson's Disease. The disease-associated immune changes of CCR2 and CD11b correlated with worse cognition. Increased TLR2 expression was related to worse motor symptoms. In conclusion, our data highlights the TLR2 relevance in the symptomatic motor presentation of the disease and a role for peripheral CD163+ and migration-competent monocytes in Parkinson's disease cognitive defects. Our study suggests that the peripheral immune system is dynamically altered in Parkinson's disease stages and directly related to both symptoms and the sex bias of the disease.

Muscle Mass and Inflammation in Older Adults: Impact of the Metabolic Syndrome.

BACKGROUND: Inflammatory processes are a cause of accelerated loss of muscle mass. Metabolic syndrome (MetS) is a highly prevalent age-related condition, which may promote and be promoted by inflammation. However, whether inflammation in MetS (metaflammation) is associated with lower muscle mass is still unclear. METHODS: Complete cross-sectional data on body composition, MetS, and the inflammatory markers interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF), and C-reactive protein (CRP) were available for 1,377 BASE-II participants (51.1% women; 68 ± 4 years old). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry. Low muscle mass (low ALM-to-BMI ratio [ALMBMI]) was defined according to the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. Regression models, adjusted for an increasing number of confounders (sex, age, physical activity, morbidities, diabetes mellitus type II, TSH, albumin, HbA1c, smoking habits, alcohol intake, education, and energy intake/day), were used to calculate the association between low ALMBMI and high inflammation (tertile 3) according to MetS. RESULTS: MetS was present in 36.2% of the study population, and 9% had low ALMBMI. In the whole study population, high CRP (odds ratio [OR]: 2.7 [95% CI: 1.6-4.7; p = 0.001]) and high IL-6 (OR: 2.1 [95% CI: 1.2-1.9; p = 0.005]) were associated with low ALMBMI. In contrast, no significant association was found between TNF, IL-10, or IL-1ß with low ALMBMI. When participants were stratified by MetS, results for IL-6 remained significant only in participants with MetS. CONCLUSIONS: Among BASE-II participants, low ALMBMI was associated with inflammation. Low-grade inflammation triggered by disease state, especially in the context of MetS, might favor loss of muscle mass, so a better control of MetS might help to prevent sarcopenia. Intervention studies to test whether strategies to prevent MetS might also prevent loss of muscle mass seem to be promising.

Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults.

BACKGROUND: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts. METHODS: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders. RESULTS: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio [HR], 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses. CONCLUSIONS: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults.

Functional Changes of T-Cell Subsets with Age and CMV Infection.

Cytomegalovirus (CMV) latent infection and aging contribute to alterations in the function and phenotype of the T-cell pool. We have demonstrated that CMV-seropositivity is associated with the expansion of polyfunctional CD57+ T-cells in young and middle-aged individuals in response to different stimuli. Here, we expand our results on the effects of age and CMV infection on T-cell functionality in a cohort of healthy middle-aged and older individuals stratified by CMV serostatus. Specifically, we studied the polyfunctional responses (degranulation, IFN-γ and TNF-α production) of CD4+, CD8+, CD8+CD56+ (NKT-like), and CD4-CD8- (DN) T-cells according to CD57 expression in response to Staphylococcal Enterotoxin B (SEB). Our results show that CD57 expression by T-cells is not only a hallmark of CMV infection in young individuals but also at older ages. CD57+ T-cells are more polyfunctional than CD57- T-cells regardless of age. CMV-seronegative individuals have no or a very low percentages of cytotoxic CD4+ T-cells (CD1017a+) and CD4+CD57+ T-cells, supporting the notion that the expansion of these T-cells only occurs in the context of CMV infection. There was a functional shift in T-cells associated with CMV seropositivity, except in the NKT-like subset. Here, we show that the effect of CMV infection and age differ among T-cell subsets and that CMV is the major driving force for the expansion of highly polyfunctional CD57+ T-cells, emphasizing the necessity of considering CMV serology in any study of immunosenescence.

T cell phenotypes associated with insulin resistance: results from the Berlin Aging Study II.

BACKGROUND: Obesity is associated with chronic low-grade inflammation leading to metabolic and cardiovascular diseases, but a subset of obese individuals is considered insulin sensitive (IS). The underlying pathophysiologic mechanisms remain elusive and clinical studies on the relationship between inflammatory markers and metabolically healthy obesity (MHO) are scarce. METHODS: In this cross-sectional analysis, we included a sample of 437 older participants (60-84 years) from the Berlin Aging Study II (BASE-II). Peripheral blood mononuclear cells were isolated, immune cell subsets were analyzed with multiparameter flow cytometry and systemic cytokine levels were measured. Immune cell parameters were correlated with metabolic measures and multiple linear regression analysis was conducted and adjusted for various demographic and clinical factors. RESULTS: We found that frequencies of naïve and memory CD4+ and CD8+ T cells inversely correlated with measures for insulin sensitivity in the older population. Moreover, the percentages of naïve CD4+ and CD8+ T cells were significantly higher, whereas activated T cells and IL-6 levels were lower in IS compared to insulin resistant (IR) obese individuals. The percentages of naïve CD4+ and CD8+ T cells were predictive for impaired insulin sensitivity (ß = 0.16, p = 0.01 and ß = 0.11, p = 0.04), and the association of naïve CD4+ T cells with insulin sensitivity persisted after multivariate adjustment (ß = 0.14, p = 0.02). CONCLUSIONS: These findings support the hypothesis that parameters of systemic inflammation can differentiate IS from IR obese individuals that are at higher risk for cardiometabolic diseases and may have clinical implications with regard to obesity treatment stratification. TRIAL REGISTRATION: DRKS00009277 . Registered 31 August 2015 - Retrospectively registered.

Alterations in Blood Monocyte Functions in Parkinson's Disease.

BACKGROUND: PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied. OBJECTIVES: The purpose of this study was to investigate the PD-related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression. METHODS: Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α-synuclein by measuring the expression of CD14, CD163, and HLA-DR and by analysis of soluble immune-related molecules in the supernatant. RESULTS: Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients' cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti-inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males. CONCLUSIONS: Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society.

No strong correlations between serum cytokine levels, CMV serostatus and hand-grip strength in older subjects in the Berlin BASE-II cohort.

Hand-grip strength is strongly correlated with measures of muscle mass and can be taken to predict morbidity and mortality. The aim of this study was to investigate the relationship between hand-grip strength and other markers associated with immune ageing, such as Cytomegalovirus (CMV) infection, leukocyte telomere length and serum levels of inflammatory and anti-inflammatory markers in the elderly. We have assessed grip strength with the Smedley Dynamometer in younger (22-37 years) and older (60-85 years) men and women in a sample of people living in Berlin (the BASE-II study). Serum cytokine levels were determined by flow-cytometry, CMV serostatus via ELISA and leukocyte telomere length by quantitative PCR. IL-1ß levels tended to be negatively associated with grip strength, but we did not find a significant association with IL-6 levels. CMV-seropositivity was not associated with higher levels of IL-1ß, IL-6 or TNF, nor with weaker grip strength in men or women at any age. A putative general measure of organismal ageing, overall leukocyte telomere length, was also found not to be associated with lower grip strength in the elderly. Hand-grip strength remains an important biomarker independent of CMV infection or shorter telomere lengths, and poorly reflected in peripheral pro-inflammatory cytokine levels, all of which have been associated in some studies with frailty and mortality.

Cytomegalovirus Infection Minimally Affects the Frequencies of B-Cell Phenotypes in Peripheral Blood of Younger and Older Adults.

BACKGROUND: An accumulation of late-differentiated CD8+ T-cells together with fewer B-cells and seropositivity for cytomegalovirus (CMV) characterises an 'immune risk profile' associated with mortality in elderly people and represents one of the hallmarks of 'immunosenescence'. OBJECTIVES: While differences in memory T-cell phenotypes between young and old people have been intensively studied, and the role of CMV is well-accepted as a driving force in this regard, the impact of CMV on B-cells, if any, has been relatively neglected thus far. METHODS: Here, we avail ourselves of blood samples from participants of the Berlin Aging Study II (BASE-II) to compare peripheral blood B-cell differentiation phenotypes of 140 age- and gender-matched CMV-seronegative or -seropositive adults aged between 24 and 85 years using multicolour flow cytometry analysis. RESULTS: We found that the frequencies of naïve B-cells within the CD19+ population were not significantly different in younger and older CMV-seronegative people. This was also true in CMV-seropositive subjects. The frequencies of late-differentiated B-cells were also not different in CMV-negative elderly and young. However, in marked contrast to the T-cell compartment, this was also true for late differentiated B-cells. Within age groups, the most marked differences in the distribution of B-cell phenotypes were between CMV-seronegative and -seropositive subjects, for both genders. CONCLUSION: These results emphasize the importance of including CMV serostatus in the analysis of immune signatures. Because the proportion of the population infected with CMV increases with age, the effect of CMV rather than age could confound analyses seeking age-associated changes to human immunity.

Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study.

Advancing age is characterized by functional and phenotypic alterations in the distribution of circulating T-cell subsets, some of which are exacerbated by a latent infection with the persistent herpesvirus, cytomegalovirus (CMV). The influence of age, sex and CMV-infection on T-cell subpopulations in the peripheral blood remains incompletely understood. Here, T cells from 157 participants of the Berlin Aging Study II (BASE-II) were characterized at 21-34 (n = 59) and 62-85 (n = 98) years of age. We found that the frequency of naïve CD8(+) T cells was significantly lower in the older group than in the young, and was different in men and women. Elderly men had a significantly lower proportion of naïve CD8(+) T cells than younger men, regardless of their CMV-status, but in older women, this was seen only in the CMV-seropositive group. Reciprocally, older men had a higher proportion of late-differentiated, potentially "senescent" CD57(+) T cells. Thus, T-cell senescence may be more pronounced in older men than women. Within the CD4(+) population, in the elderly of both sexes there was a significantly higher proportion of late-differentiated TEMRA cells (T effector memory cells re-expressing CD45RA), but these were present exclusively in CMV-positive subjects. Finally, for the first time, we examined the so-called TSCM cell (T-stem cell-like memory) subpopulations in both CD4(+) and CD8(+) subsets and found that neither CMV-seropositivity nor age or sex affected their frequencies. This study confirms significant cross-sectional age-associated differences of T-cell subset distribution in a representative German urban population and emphasizes the impact of both sex and CMV-infection on T-cell naïve and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells.

Multi-parametric phospho-flow cytometry: a crucial tool for T lymphocyte signaling studies.

Tools such as protein immunoblotting have proven benefits for investigating T lymphocyte signaling but have several drawbacks such as the number of cells required and the difficulty of distinguishing subset-specific differences without expensive and invasive cell sorting. Recent advances in immunology and the identification of T lymphocyte sub-populations making up only a very small fraction of the total population highlight the importance of studying signaling in those small subsets in a feasible, cost-effective, high-throughput manner. To this end, we have developed a simplified protocol to study both intracellular phosphorylation patterns of important signal transduction molecules concomitantly with T cell surface marker expression. A multi-parametric analysis may allow the quantification of the phosphorylation of up to five signaling molecules in CD4 and CD8 T lymphocytes and their naïve, central memory, effector memory, and TEMRA subsets. This enables precise identification of subset-specific signaling and alterations of signaling pathways in physiological and pathological situations. The importance of such detailed analysis is discussed.

Flow cytometric lymphocyte subset analysis using material from frozen whole blood.

Multicenter immune monitoring programs commonly rely on storing and shipping cryopreserved peripheral blood mononuclear cells (PBMC), isolated from whole blood before freezing. However, under many conditions in the field, facilities to separate PBMC are absent. Here, we investigate the feasibility of using whole blood (WB) frozen at -80°C as a source of viable lymphocytes for use in immunological studies. We compare the percentage of CD4 and CD8 T lymphocytes and their subsets from frozen WB with results from cryopreserved PBMC in five random healthy blood donors (three female, two male). We report that CD4 and CD8 values in lymphocytes from WB frozen up to 120 days were very similar to those of PBMC frozen up to 10 days. These data suggest that within the limits of parameters investigated in this study, contrary to our original assumptions, whole blood frozen at -80°C may in fact be an appropriate source of viable lymphocytes for T cell enumeration assays in immunological and epidemiological studies.

Impact of Cytomegalovirus Infection and Genetic Background on the Frequencies of Peripheral Blood Suppressor Cells in Human Twins.

Frequencies and proportions of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in peripheral blood may be informative biomarkers for certain disease states. The influence of genetics and lifetime pathogen exposures on Treg and MDSC frequencies is largely unexplored. Cytomegalovirus (CMV) establishes a latent infection and causes an accumulation of late-differentiated CD8+ memory T cells, commonly associated with a lower frequency of naive cells. Here, analyzing peripheral blood mononuclear cells by multicolor flow cytometry, we found a tendency towards lower frequencies of CD4+CD25+FoxP3+ Tregs in CMV-seropositive than -seronegative middle-aged individuals (p = 0.054), whereas frequencies of lineage-negative CD14+HLA-DR-MDSCs were significantly lower in CMV-seropositive participants (p = 0.005). Assessing associations with the presence of antibodies against different CMV structural proteins, rather than merely assigning seropositivity or seronegativity, failed to yield any closer associations. Examining Treg subsets revealed at most a minor role of the individual's genetic background, based on an analysis of monozygotic (MZ, n = 42) versus dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry. The same was true for MDSCs. These initial results suggest that an immunological history of exposures is more important than genetics in determining overall human suppressor cell levels.

Cellular Immune Phenotypes and Worsening Scores of Frailty-Associated Parameters Over an 18-Month Period in the Very Old.

Frailty has been related to inflammaging and certain immune parameters. In previous analyses of participants older than 80 years of age in the longitudinal BELFRAIL cohort study, the main focus was on T-cell phenotypes and the association with cytomegalovirus (CMV) serostatus and survival, finding that a CD4:CD8 ratio greater than 5 was associated with frailty, impaired activities of daily living (ADLs), and mortality (but only in women). Here, we phenotyped peripheral blood immune cells via multicolor flow cytometry and correlated these with the dynamics of changes in ADL, geriatric depression score, Mini-Mental State Examination, and Short Physical Performance Battery from baseline values over 18 months follow-up. We found that higher frequencies of B cells and late-differentiated CD8+ T cells at 18 months from baseline were associated with ADL impairment that had worsened over the preceding 18 months. There were no significant associations with monocyte, dendritic cell, or natural killer (NK) cell phenotypes. No associations with the Geriatric Depression Scale, the Mini-Mental State Examination, or the Short Physical Performance Battery were found. Thus, while these results do not establish causality, they suggest that certain adaptive immune, but not innate immune, parameters are associated with a worsened ADL in the very old.

Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer's disease.

The distribution of peripheral T cell subsets in young and healthy old people is markedly different, characterized by decreased numbers of naïve cells and increased numbers and clonal expansions of memory cells, predominantly in the CD8+ MHC class I-restricted subset. Here, however, we document dramatic alterations in naïve and memory subsets of CD4+ cells in patients with mild Alzheimer's disease (AD), with greatly decreased percentages of naïve cells, elevated memory cells, and increased proportions of CD4+ but not CD8+ cells lacking the important costimulatory receptor CD28. CD4+CD25(high) potentially T regulatory cells with a naïve phenotype are also reduced in AD patients. Together these data provide stronger evidence than hitherto presented for more highly differentiated CD4+ as well as CD8+ T cells in AD patients, consistent with an adaptive immune system undergoing persistent antigenic challenge and possibly manifesting dysregulation as a result.

Are skin senescence and immunosenescence linked within individuals?

With advancing age, many organs exhibit functional deterioration. The age-associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle-aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4+ nor CD8+ T-cell immunosenescence phenotype composites (i.e., end-stage differentiated/senescent T cells, including CD45RA+ CCR7- CD28- CD27- CD57+ KLRG1+ T cells). Dermal p16INK4a positivity was significantly associated with the CD4+ , but not with the CD8+ immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals.

Establishment of Systems to Enable Isolation of Porcine Monoclonal Antibodies Broadly Neutralizing the Porcine Reproductive and Respiratory Syndrome Virus.

The rapid evolution of porcine reproductive and respiratory syndrome viruses (PRRSV) poses a major challenge to effective disease control since available vaccines show variable efficacy against divergent strains. Knowledge of the antigenic targets of virus-neutralizing antibodies that confer protection against heterologous PRRSV strains would be a catalyst for the development of next-generation vaccines. Key to discovering these epitopes is the isolation of neutralizing monoclonal antibodies (mAbs) from immune pigs. To address this need, we sought to establish systems to enable the isolation of PRRSV neutralizing porcine mAbs. We experimentally produced a cohort of immune pigs by sequential challenge infection with four heterologous PRRSV strains spanning PRRSV-1 subtypes and PRRSV species. Whilst priming with PRRSV-1 subtype 1 did not confer full protection against a subsequent infection with a PRRSV-1 subtype 3 strain, animals were protected against a subsequent PRRSV-2 infection. The infection protocol resulted in high serum neutralizing antibody titers against PRRSV-1 Olot/91 and significant neutralization of heterologous PRRSV-1/-2 strains. Enriched memory B cells isolated at the termination of the study were genetically programmed by transduction with a retroviral vector expressing the Bcl-6 transcription factor and the anti-apoptotic Bcl-xL protein, a technology we demonstrated efficiently converts porcine memory B cells into proliferating antibody-secreting cells. Pools of transduced memory B cells were cultured and supernatants containing PRRSV-specific antibodies identified by flow cytometric staining of infected MARC-145 cells and in vitro neutralization of PRRSV-1. Collectively, these data suggest that this experimental system may be further exploited to produce a panel of PRRSV-specific mAbs, which will contribute both to our understanding of the antibody response to PRRSV and allow epitopes to be resolved that may ultimately guide the design of immunogens to induce cross-protective immunity.

Frequencies of peripheral immune cells in older adults following seasonal influenza vaccination with an adjuvanted vaccine.

As age increases, immune responses and consequently protection following vaccination to seasonal influenza is commonly believed to decrease. Possible drivers of this immune dysfunction include immunosenescence, repeated exposure to the same seasonal influenza antigens, and prior infection with cytomegalovirus (CMV). Here, to determine immune parameters distinguishing vaccine humoral responders (R) from non-responders (NR) following vaccination, we surveyed broad peripheral blood "cellular immune correlates" of older adults vaccinated with Fluad® (an adjuvanted subunit influenza vaccine containing strains H1N1, H3N2 and B). Phenotyping included αß-T-cells, γδ-T-cells, B-cells and myeloid cells. The frequencies of most of these lymphocyte phenotypes were found to be similar in R and NR, although perhaps counterintuitively, one of the few differences seen between the two groups was higher frequencies of regulatory T-cells in R. These differences were more prominent for responses to the vaccine strains H1N1 and H3N2 than to the B strain, and in CMV-seropositive than CMV-seronegative elderly. Further, frequencies of early-differentiated CD4+ T-cells tended to be higher and frequencies of memory CD4+ T-cells tended to be lower in R than NR. There were also differences in B-cells, with higher frequencies in R compared to NR. To the best of our knowledge, these results are the first to report such differences in elderly people responding or failing to respond to adjuvanted seasonal influenza vaccination.

Peripheral Immune Signatures in Alzheimer Disease.

According to the current paradigm, the main cause of AD is the accumulation of neurotoxic amyloid beta (Aß) peptide aggregates resulting from the cleavage of the amyloid precursor protein into peptides of different length, with the 42 amino acid long Aß42 being the most toxic form. Aß can aggregate and form plaques in the brain. It further promotes the hyperphosphorylation of the tau protein which forms characteristic neurofibrillary tangles and thereby loses its important role in axonal transport and contributes to neurodegeneration. Therefore, treatments have targeted Aß, but clinical trials of immunotherapies caused severe side effects and showed that Aß clearance alone did not result in any cognitive improvement. This leads to the question: what else promotes AD pathology? Here, we review data on systemic inflammation and the possible roles that the immune system might play in AD. Microglia and astrocytes are activated and secrete inflammatory cytokines and chemokines. Via a disturbed blood-brain barrier, peripheral immune cells are activated and recruited towards inflamed brain lesions and amyloid plaques, but due to the chronic nature of the amyloid burden and their reduced function, these cells are not able to control inflammation and the associated detrimental immune responses. In addition, age-related inflammation and chronic infection with herpes viruses might contribute to the systemic inflammation and exacerbate attempts to restore the balance of inflammation.

Altered dendritic cell subset distribution in patients with Parkinson's disease: Impact of CMV serostatus.

Parkinson's disease (PD) is characterised by low-level systemic inflammation, which may be at least partly due to pathophysiological activation of immunity. Here, the frequencies of different types of circulating dendritic cells (DCs) with and without a pro-inflammatory phenotype were determined in PD patients and controls. A high proportion of older people is infected with cytomegalovirus (CMV), which acts as a chronic antigenic stressor that could also contribute to increased inflammation. Following this idea, we found higher frequencies of myeloid DCs with a pro-inflammatory CD16+ILT2(high) phenotype in CMV-positive PD patients than controls, suggesting the potential involvement of CMV in exacerbating PD.