People living with HIV-1 (PLWH) are a population at higher risk for communicable disease and therefore a target group for vaccination. Owing to the success of anti-retroviral therapy, PLWH live longer, but face new challenges related to ageing, which add to their underlying immunodeficiencies. We review here the immune dysregulations occurring with chronic HIV-1 infection and ageing in the era of antiretroviral therapy, focusing on cellular mechanisms that can explain the lower immune response to most vaccines in older treated PLWH, and we discuss potential developments to improve vaccination strategies in this specific population.
Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features. CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers. Our findings reinforce the association between CD57 expression, T cell differentiation, and CMV seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for CMV serostatus to avoid misleading conclusions, especially in oncology and ageing research.
Sjögren's syndrome (SS) is an autoimmune disease primarily affecting exocrine glands, characterized by dry mouth and eyes, with an unclear pathogenesis. Recent studies suggest that salivary gland (SG) cell senescence is critical in SS pathogenesis. The senescence mechanism may serve as a critical pathological nexus linking molecular abnormalities to clinical phenotypes. Under assaults from infections, environmental factors, and immune dysregulation, SG cells undergo oxidative stress, telomere shortening, and DNA damage, leading to senescence. Senescent cells lose proliferative capacity and secrete senescence-associated cytokines, triggering inflammation and immune responses that exacerbate disease progression. Elucidating the mechanisms of SG cell senescence may advance our understanding of SS pathogenesis and identify novel therapeutic targets, offering new avenues for SS treatment.
Immunosenescence is the gradual deterioration in the functionality of the immune system that has various clinical manifestations, such as a weakened response to vaccination, higher susceptibility to viral/bacterial/fungal infection, and higher incidence rates regarding the ageing-based disorders. Conventionally used models, like animal or 2D models for unraveling the interactions between ageing and immunity are unable to depict the complexity of bodily environments. However, this major limitation can be addressed via using the organoid technology. For clarification, organoids are tissue-resembling 3D structures that are generated from stem cells; they have the major superiority of preserving the human physiology, multicellular intricateness, and the capability of dynamic interactions between the existing elements. Organoid-based technology has been applied for the study of different organ-specific immunosenescence, such as in the intestine, brain, liver, and skin. Besides, organoids offer the bright innovative future of senolytic CAR T lymphocytes and other regenerative-based therapies. This review narrates the cutting-edge application of organoids and the mechanisms involved in the detailed molecular processes of organ-specific immunosenescence.
Background: Amidst the ongoing COVID-19 pandemic, understanding factors that influence vaccine efficacy is crucial, particularly in older adults. Regular physical exercise and/or structured physical activity (SPA) has emerged as a potential modulator of immune responses, enhancing vaccine effectiveness. This systematic review aims to consolidate current evidence on the impact of SPA/exercise on both immune and inflammatory responses to COVID-19 vaccination in adults and older individuals.
Methods: Most relevant studies were extracted from indexed databases using health subject terms in English, Portuguese, and Spanish. Studies that examined the impact of regular exercise or SPA on inflammatory and/or immunological responses in relation to COVID-19 immunization were selected. In particular, all chosen studies included individuals who received vaccinations either prior to or following the exercise regimen or SPA, and the main goal was to evaluate these effects on immunological and/or inflammatory reactions induced by vaccination.
Results: Among the 7 studies included (n = 1149), the effects of regular exercise or PA on vaccine-induced immune responses while concurrently assessing inflammatory markers were examined. The findings suggest that moderate to high-intensity structured physical activity (50-70% of maximum heart rate for aerobic exercise and 60-80% of 1RM for resistance training), performed 3-5 times per week, was able to enhance immune responses to COVID-19 vaccination, particularly by mitigating chronic low-grade inflammation. Acute exercise can transiently boost immunity, whilst engagement in moderate SPA over a period of six months may contribute to sustained improvements in immune function, especially in older adults. However, these findings should be interpreted with caution due to variability in study design, sample characteristics, and potential confounding factors.
Conclusion: Regular exercise and SPA play a significant role in improving immune/inflammatory responses to COVID-19 vaccination. Older adults, in particular, may benefit from regular SPA and exercise as a strategy to counteract immunosenescence and optimize vaccine efficacy. However, further research is needed to better refine exercise protocols and determine long-term benefits in different populations.
Sarcopenia and atherosclerosis are prevalent age-related conditions increasingly recognized as interconnected through shared immune-mediated pathways. This review elucidates how "inflammaging" driven by dysregulated immune responses. Key age-related mechanisms include macrophage polarization imbalance, T/B cell dysregulation, and activation of pro-inflammatory signaling pathways. These processes promote oxidative stress, insulin resistance, creating a vicious cycle that exacerbates muscle and vascular decline. Emerging therapeutic strategies offering potential for dual-benefit interventions. Understanding these immune interactions provides a foundation for integrated approaches to mitigate sarcopenia and atherosclerosis in aging.
Ageing is a well-recognised factor influencing immune competence; however, elderly individuals remain underrepresented in clinical trials, resulting in gaps in our understanding of their immune responses to disease. To address this gap, we investigated circulating soluble immune checkpoints (sICs) and cytokines in the elderly and middle-aged individuals, both healthy and patients with colorectal cancer (CRC). Our findings revealed a decline in sICs and cytokine levels in healthy elderly individuals compared to their middle-aged counterparts. Key analytes -Galectin-9, sLAG-3, sPD-L1 and sTIM-3- effectively distinguished age groups in healthy volunteers (HVs). However, these differences were not observed when applying this signature in CRC patients, where the combined analysis of plasma Galectin-9, IL-10 and CXCL10 did reliably discriminate between elderly CRC patients and age-matched HVs. This result highlights the potential of these immunological factors as non-invasive biomarkers for cancer detection in this population. In contrast, a much larger number of soluble markers was needed to distinguish CRC patients from HVs among the middle-aged. Collectively, these findings underscore the relevance of observing age stratification for biomarker discovery and lay the groundwork for further exploration of soluble immune mediators in ageing related to tumour pathophysiology.
Objective: To investigate the distribution characteristics of peripheral blood lymphocyte subsets in elderly psoriasis patients and analyze the interactions between immunosenescence and psoriasis and their impact on immune cell subpopulations.
Methods: This cross-sectional study enrolled 318 psoriasis patients and 167 healthy controls, stratified by age into elderly (≥ 65 years) and non-elderly (18-64 years) groups. Peripheral blood lymphocyte subsets, including CD3+ T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells, were analyzed using four-color flow cytometry. Generalized linear models were employed to analyze associations between PASI scores and lymphocyte subsets, and correlation network analysis was constructed to evaluate interaction patterns among immune cell populations.
Results: The elderly psoriasis group demonstrated significantly reduced CD8+ T cell percentage compared to controls (24.52% vs. 28.62%, P < 0.001), accompanied by an elevated Th/Ts ratio (1.57 vs. 1.27, P < 0.001) and significantly increased NK cell percentage and absolute count. Generalized linear modeling revealed a significant negative interaction effect between psoriasis and age on CD8+ T cell percentage (β = -3.979, P = 0.019), while the Th/Ts ratio exhibited a significant positive interaction effect (β = 0.230, P = 0.010). B cell absolute count showed a positive correlation with PASI score (r = 0.180, P = 0.001), with this correlation being more pronounced in elderly patients (r = 0.308, P = 0.014). Network analysis demonstrated reduced connectivity density among immune cell subpopulations in elderly patients.
Conclusions: Elderly psoriasis patients exhibit age-related alterations in peripheral blood lymphocyte subset distribution, characterized by decreased CD8+ T cells, elevated Th/Ts ratio, and increased NK cells. B cells may serve as potential biomarkers for assessing disease severity in elderly psoriasis patients.
Influenza viruses remain a significant threat to both animals and public health. Each season influenza virus infection causes significant morbidity and mortality, especially in the elderly population. Annual vaccination boosts antibody titers against circulating influenza strains in elderly individuals, albeit the antibody responses are not as robust as those in younger adults. In addition, the elderly have a rapid decline in antibody titers over a 6-month period following an influenza virus immunization with antibody titers often returning to baseline at the beginning of each influenza season. Thus, there is a need for next-generation influenza vaccines that induce broadly and long-lasting protective immunity against influenza viruses in high-risk, elderly populations. In this study, Computationally Optimized Broadly Reactive Antigen (COBRA)-based H1 and H3 hemagglutinin (HA) vaccines were tested in combination with toll-like receptor (TLR) agonists as adjuvants in elderly ferrets with immune memory to historical influenza viruses to assess the breadth of protective antibody responses. These COBRA vaccines were mixed with either TRAC478, which is a combination of two TLR agonists, INI-2002 (a synthetic TLR4 agonist) and INI-4001 (a synthetic TLR7/8 agonist), or SAS, which is a mixture of INI-2002 and a semi-synthetic saponin. Elderly ferrets vaccinated with H1/H3 COBRA HA proteins plus TRAC478, or SAS had antibodies with hemagglutination-inhibition (HAI) activity against a panel of H1N1 and H3N2 influenza viruses that were significantly higher than animals vaccinated with unadjuvanted HA vaccine only. These elderly ferrets were protected following challenge with influenza virus with little to no detectable signs of disease or weight loss. In addition, there were reduced viral titers detected in nasal washes compared to elderly ferrets vaccinated with unadjuvanted HA proteins. Overall, both TRAC478 and SAS were effective adjuvants to enhance protective antibodies in elderly ferrets compared to animals that were vaccinated with only COBRA HA protein.
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