Discrimination between CMV infection and Alzheimer's disease as driving forces for immune senescence

This study investigated the immune profiles of patients with dementia. The focus of this study was on leukocyte populations found in the blood. Initial experiments assessed the frequency of major leukocyte subsets in AD patients and healthy controls, but no differences were observed - the frequencies of B-cells, NK-cells and NKT-like cells were similar for all groups. The monocyte marker CD14 tended to be less frequently expressed in control subjects compared to AD patients, but the results differed across the cohorts that were studied. In the second phase of this study, the phenotype of different leukocyte populations was analysed. B-cells showed a tendency towards a lowered frequency of CD27-IgD+ naïve cells in AD patients compared to healthy controls. This trend was even more pronounced for T-cells, notably in the case of CD4+ T-cells. The frequencies of Naïve CD4+ T-cells were lower in AD patients than in controls in pilot studies as well as larger cohorts. Parallel to this, the percentages of late-differentiated CD4+ T-cells were found elevated in AD patients. In addition, the frequency of CD57- and KLRG-positive cells tended to be greater in patients than controls, but these differences were only statistically significant in some cohorts. Another observation, indicative of immune exhaustion, was an increased level of PD-1 in T-cells of AD patients compared with controls, although this was also not statistically significant. The question remains, which is the factor causing these immune changes in AD. One possible explanation is that Aβ is causing chronic antigenic stress and driving T-cell differentiation. Further studies investigated chemokine receptor expression. In AD, a compromised and potentially leaky blood-brain barrier results in an exchange between the periphery and the brain that does usually not occur. A consequence is that cytokines, Aβ protein and cells may migrate through the BBB contributing to systemic inflammation. One aspect of AD pathology is the potential recruitment of immune cells to the brain. To elucidate the mechanisms behind these processes, the frequency of peripheral leukocytes expressing CCR2, CCR4, CCR5 and CCR6 was determined. The results indicated that leukocytes from AD patients more frequently expressed these proteins, although the differences were not always statistically significant in all cohorts. In the case of CCR6, it was observed that this receptor was not only more often expressed on a single leukocyte subset, but expressed more frequently on B-cells, monocytes, CD4+ and CD8+ T-cells as well. In conclusion, this work provides evidence that hints toward a more differentiated and exhausted immune system in AD patients. What still remains unclear is whether the recruitment of immune cells to the brain is a consequence or cause of the disease. Experiments using in vitro models where the entry of immune cells to the brain can be blocked may provide insight into this lingering question. These experiments may also assist in determining if the migration of immune cells results in beneficial effects, for example by phagocytosing Aβ protein, or if they function to promote disease progression assuming that in vitro models accurately parallel human disease. A way of investigating this could be to enhance the chemokine gradient in vivo, as the immune cells examined in this study demonstrated increased CCR expression. In the event that immune cells are found to promote AD, it may be possible to treat patients with CCR-blockers in order to reduce immune cell migration to the brain. Using this approach, it may be possible to selectively block B-cell migration as they were observed to express CCR6, but not CCR4 or CCR5. After determining which leukocyte subset contributes to the promotion of disease, it may be possible to employ antibodies specific to CCRs that are predominately expressed on this subset. It is hypothesised that a rejuvenation of the immune system may be beneficial for AD patients. This might be achieved through improving Aβ clearance, possibly by enhancing monocyte migration from the periphery to the brain. Reduced Aβ load may result in reduced T-cell differentiation, i.e. fewer memory T-cells and more naïve T-cells. It is thought that in AD patients as in healthy elderly CMV is the driving force of CD8+ T-cell differentiation and Aβ may have a similar effect. Whether the effects of CMV and Aβ are additive remains to be determined. A larger cohort of study participants - as recruited here - including sufficient CMV- and CMV+ AD patients and controls would be necessary to investigate this. This question may be of particular importance given that CMV may contribute to inflammation in AD and thus provide another burden to the functioning of the immune system thereby decreasing the ability of the body to control the disease. The role that CMV may play in the functional decline of the immune system may also be related to cognitive decline, such as that in AD

Higher Lipoprotein (a) Levels Are Associated with Better Pulmonary Function in Community-Dwelling Older People - Data from the Berlin Aging Study II

Reduced pulmonary function and elevated serum cholesterol levels are recognized risk factors for cardiovascular disease. Currently, there is some controversy concerning relationships between cholesterol, LDL-cholesterol, HDL-cholesterol, serum triglycerides and lung function. However, most previous studies compared patients suffering from chronic obstructive pulmonary disease (COPD) with healthy controls, and only a small number examined this relationship in population-based cohorts. Moreover, lipoprotein a [Lp(a)], another lipid parameter independently associated with cardiovascular diseases, appears not to have been addressed at all in studies of lung function at the population level. Here, we determined relationships between lung function and several lipid parameters including Lp(a) in 606 older community-dwelling participants (55.1% women, 68±4 years old) from the Berlin Aging Study II (BASE-II). We found a significantly lower forced expiration volume in 1 second (FEV1) in men with low Lp(a) concentrations (t-test). This finding was further substantiated by linear regression models adjusting for known covariates, showing that these associations are statistically significant in both men and women. According to the highest adjusted model, men and women with Lp(a) levels below the 20th percentile had 217.3ml and 124.2ml less FEV1 and 239.0ml and 135.2ml less FVC, respectively, compared to participants with higher Lp(a) levels. The adjusted models also suggest that the known strong correlation between pro-inflammatory parameters and lung function has only a marginal impact on the Lp(a)-pulmonary function association. Our results do not support the hypothesis that higher Lp(a) levels are responsible for the increased CVD risk in people with reduced lung function, at least not in the group of community-dwelling older people studied here

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

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