One-Year Consumption of a Mediterranean-Like Dietary Pattern With Vitamin D3 Supplements Induced Small Scale but Extensive Changes of Immune Cell Phenotype, Co-receptor Expression and Innate Immune Responses in Healthy Elderly Subjects:Results From the United Kingdom Arm of the NU-AGE Trial

Amongst the major features of aging are chronic low grade inflammation and a decline in immune function. The Mediterranean diet (MedDiet) is considered to be a valuable tool to improve health status, and although beneficial effects have been reported, to date, immunological outcomes have not been extensively studied. We aimed to test the hypothesis that 1 year of a tailored intervention based on the MedDiet with vitamin D (10 μg/day) would improve innate immune responses in healthy elderly subjects (65–79 years) from the English cohort (272 subjects recruited) of the NU-AGE randomized, controlled study (clinicaltrials.gov, NCT01754012). Of the 272 subjects forming the United Kingdom cohort a subgroup of 122 subjects (61 in the intervention group and 61 in the control group) was used to evaluate ex vivo innate immune response, phenotype of circulating immune cells, and levels of pro- and anti-inflammatory markers. Odds Ratio (OR) was calculated for all the parameters analyzed. After adjustment by gender, MedDiet-females with a BMI < 31 kg/m2 had a significant upregulation of circulating CD40+CD86+ cells (OR 3.44, 95% CI 1.01–11.75, P = 0.0437). Furthermore, in all MedDiet subjects, regardless of gender, we observed a MedDiet-dependent changes, although not statistically significant of immune-critical parameters including T cell degranulation, cytokine production and co-receptor expression. Overall, our study showed that adherence to an individually tailored Mediterranean-like dietary pattern with a daily low dose of vitamin D3 supplements for 1 year modified a large variety of parameters of immune function in healthy, elderly subjects. We interpreted these data as showing that the MedDiet in later life could improve aspects of innate immunity and thus it could aid the design of strategies to counteract age-associated disturbances

Nutrition, diet and immunosenescence

Ageing is characterized by immunosenescence and the progressive decline in immunity in association with an increased frequency of infections and chronic disease. This complex process affects both the innate and adaptive immune systems with a progressive decline in most immune cell populations and defects in activation resulting in loss of function. Although host genetics and environmental factors, such as stress, exercise and diet can impact on the onset or course of immunosenescence, the mechanisms involved are largely unknown. This review focusses on identifying the most significant aspects of immunosenescence and on the evidence that nutritional intervention might delay this process, and consequently improve the quality of life of the elderly

How Can the Health System Retain Women in HIV Treatment for a Lifetime? A Discrete Choice Experiment in Ethiopia and Mozambique

Introduction: Option B+, an approach that involves provision of antiretroviral therapy (ART) to all HIV-infected pregnant women for life, is the preferred strategy for prevention of mother to child transmission of HIV. Lifelong retention in care is essential to its success. We conducted a discrete choice experiment in Ethiopia and Mozambique to identify health system characteristics preferred by HIV-infected women to promote continuity of care. Methods: Women living with HIV and receiving care at hospitals in Oromia Region, Ethiopia and Zambézia Province, Mozambique were shown nine choice cards and asked to select one of two hypothetical health facilities, each with six varying characteristics related to the delivery of HIV services for long term treatment. Mixed logit models were used to estimate the influence of six health service attributes on choice of clinics. Results: 2,033 women participated in the study (response rate 97.8% in Ethiopia and 94.7% in Mozambique). Among the various attributes of structure and content of lifelong ART services, the most important attributes identified in both countries were respectful provider attitude and ability to obtain non-HIV health services during HIV-related visits. Availability of counseling support services was also a driver of choice. Facility type, i.e., hospital versus health center, was substantially less important. Conclusions: Efforts to enhance retention in HIV care and treatment for pregnant women should focus on promoting respectful care by providers and integrating access to non-HIV health services in the same visit, as well as continuing to strengthen counseling

Age-Associated Decline in Dendritic Cell Function and the Impact of Mediterranean Diet Intervention in Elderly Subjects

Introduction: Aging is accompanied by increased susceptibility to infection and age-associated chronic diseases. It is also associated with reduced vaccine responses, which is often attributed to immunosenescence and the functional decline of the immune system. Immunosenescence is characterized by a chronic, low-grade, inflammatory state termed inflammaging. Habitants of Mediterranean (MED) regions maintain good health into old age; often attributed to MED diets. Hypothesis: Adoption of a MED-diet by elderly subjects, in Norfolk (UK), may improve immune responses of these individuals and in particular, dendritic cell (DC) function. Experimental approach: A total of 120 elderly subjects (65–79 years old) recruited onto the Nu-AGE study, a multicenter European dietary study specifically addressing the needs of the elderly, across five countries, and were randomized to the control or MED-diet groups, for one year. Blood samples were taken pre- and post-intervention for DC analysis and were compared with each other, and to samples obtained from 45 young (18–40 years old) subjects. MED-diet compliance was assessed using high performance liquid chromatography-with tandem mass spectrometry analysis of urine samples. Immune cell and DC subset numbers and concentrations of secreted proteins were determined by flow cytometric analysis. Results: As expected, reduced myeloid DC numbers were observed in blood samples from elderly subjects compared with young. The elevated secretion of the adipokine, resistin, after ex vivo stimulation of peripheral blood mononuclear cells from elderly subjects, was significantly reduced after MED-diet intervention. Conclusion: This study provides further evidence of numerical and functional effects of aging on DCs. The MED-diet showed potential to impact on the aging immune cells investigated and could provide an economical approach to address problems associated with our aging population

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

The lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists

Plasmacytoid DC from Aged Mice Down-Regulate CD8 T Cell Responses by Inhibiting cDC Maturation after Encephalitozoon cuniculi Infection

Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations

Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity

Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly

Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity