Immunity & Ageing最新文献

Background: Recent studies have suggested that gestational diabetes mellitus (GDM) can accelerate cellular aging in multiple cell types in offspring, but its impact on immune senescence remains uncertain. Our prior study reveals GDM increased the secretion of inflammatory factors by monocytes in offspring. This study discovered the transcriptome characteristics of aging monocytes at the single-cell level and explore the impact of GDM on the progression of monocyte aging in offspring.

Method: Single-cell sequencing data from 56 healthy individuals (aged 0-100 years), comprising self-measured samples (n = 6) and publicly available datasets from the Gene Expression Omnibus (GEO, n = 50), were analyzed to characterize monocyte senescence. Linear mixed-effects modeling was used to screen for age-related genes. A random forest model was created to predict immune age in monocytes, allowing for quantitative assessment of aging.

Results: We detected an increase in the number of inflammatory monocytes expressing IL1B and CXCL8 with age. Two age-related gene expression patterns were identified in monocytes. Analysis of offspring monocytes from mothers with GDM suggested that exposure to a GDM environment in the womb may lead to increased expression of aging-related genes, a hindered cell cycle, and increased immune age. The immune age of monocytes at birth is significantly linked to maternal weight gain, high fasting blood glucose levels, and cord blood C-peptide levels during pregnancy.

Conclusions: Exposure to GDM during pregnancy accelerates aging in offspring immune cells. Monitoring maternal weight and blood sugar during GDM can help prevent negative effects on the offspring immune system.

Background: Elderly individuals face heightened susceptibility to infectious diseases and diminished vaccine responses. Vaccine adjuvants offer a solution. Despite aluminum adjuvant's long history, its limitations in inducing strong cellular immunity and protecting immunocompromised individuals restrict its application. Building upon our previous development of zinc salt particle-based risedronate (Zn-RS), we systematically investigated the immunoenhancing effects of Zn-RS in aged mice and thoroughly explored the underlying mechanisms responsible for these observations in this study.

Results: Compared to formulations using aluminum adjuvant, Zn-RS combined with either varicella-zoster virus glycoprotein E (gE) or SARS-CoV-2 monovalent STFK protein (STFK) elicited significantly higher IgG and neutralization titers, as well as superior long-term humoral immunity. Moreover, Zn-RS induced greater quantities of dendritic cells (DCs), antigen-presenting cells (APCs), follicular helper T (T_FH) cells, Th1/Th2/Th9/Th17 type immune cells, germinal center B cells (GCBs) and plasma cells.

Conclusions: These findings support Zn-RS as a promising adjuvant candidate for elderly populations, warranting further exploration of its mechanisms and potential applications.

Objective: There are no published data on the associations between plasma concentration of pentraxin-3 (PTX-3) - a marker of vascular inflammation and mortality in older subjects with or without metabolic syndrome (MS). Therefore, we aimed to compare the prognostic significance of increased PTX-3 and CRP levels on overall survival in subjects aged 60 and older with and without MS.

Materials and methods: Study participants (N = 3534) were categorized according to the presence or absence of MS and then each of these groups was stratified into 3 subgroups based on concentrations of CRP (≤ 3 mg/dL and > 3 mg/dL) and PTX-3 (< and ≥ the sex-specific cut-off values, based on the ROC curve analysis with the Youden index): double-negative inflammatory markers (low CRP and PTX-3 plasma concentrations); single-positive inflammatory marker (increased CRP or PTX-3 plasma concentrations) and double-positive inflammatory markers subgroup (increased CRP and PTX-3 plasma concentrations). During the 4.19-year follow-up, 678 (19.2% of the entire cohort) individuals died including 401 men (22.9%) and 277 women (15.5% ).

Results: The optimal cut-off for PTX-3 plasma concentration associated with an increased risk of death was 2.07 ng/mL for men and 2.23 ng/mL for women. The death rates were increased for single-positive and were highest in double-positive subgroups both for men and women, with or without MS. Kaplan-Meier analysis showed no effect of MS on survival in men and women in subgroups within specific inflammatory marker categories. Of note, the inflammatory markers class effect on survival was already significant in the single-positive subgroups (34% and 44% higher risk for death for men and women), and even more pronounced for the double-positive subgroup (more than two and almost three times higher risk of death for men and women, respectively). In the entire study group, a weak correlation was found between plasma concentrations of PTX-3 and hs-CRP (ρ = 0.11, p < 0.001) and slightly higher in undernourished subjects with hs-CRP > 3 mg/dL (ρ = 0.28, p < 0.001).

Conclusion: Our study suggests that in the age-advanced Caucasian population, the inflammatory status with increased plasma levels of both PTX-3 and CRP is associated with a higher risk of all-cause mortality, regardless of the occurrence of MS. However, due to the retrospective study design, these results require confirmation in prospective studies with an analysis of the underlying causes of death.

Neuroinflammation is a key contributor to the onset and progression of neurodegenerative diseases, driven by factors such as viral infections, autoimmune disorders, and peripheral inflammation. However, the mechanisms linking peripheral inflammation or viral infections to neuroinflammation remain poorly understood, limiting the development of effective therapies. Proinflammatory cytokines are implicated in these processes but their effects on brain cells, including microglia, remain insufficiently characterized. Here, we demonstrate that IL-21, a proinflammatory cytokine elevated in autoimmune disorders, chronic viral infections, and Alzheimer's disease, activates microglia and promotes lipid accumulation within these cells. Young, healthy mice injected with IL-21 to mimic chronic exposure exhibited increased proinflammatory cytokine levels and microglial activation in the brain. Notably, microglia in these mice displayed enhanced lipid accumulation, accompanied by upregulation of lipid uptake receptors such as CD36 and TREM-2. These findings were corroborated using the human microglial cell line HMC-3, where IL-21 exposure similarly induced lipid accumulation and increased expression of CD36 and ApoE. Mechanistic investigations revealed that IL-21 upregulates HIF-1α, a transcription factor critical for lipid metabolism and lipid droplet formation. Additionally, we observed elevated IL-21 levels in the circulation of elderly individuals compared to younger counterparts, with IL-21 increases associated with CMV seropositivity. Aged mouse brains mirrored the microglial lipid accumulation and activation patterns seen in IL-21-injected mice. In summary, we identify a novel IL-21-driven mechanism involving lipid accumulation in microglia that contributes to neuroinflammation.

Background: Ageing-associated remodeling of the murine B cell system is accompanied with a reduction of CD19⁺ B cells such as follicular B cells (FOB) and an accumulation of age-associated B cells (ABC) or activated B cell subsets. This remodeling is thought to confer an attenuated antibody response, such as to SARS-CoV-2 spike (S) vaccines in both aged mice and humans. To gain insight into the de novo development and function of an old B cell system, we reconstituted young and old immune systems by transferring hematopoietic stem cells (HSCs) from immune-competent young (2-3 months) CD45.1⁺ donors (DY-HSC) or old (20-24 months) donors (DO-HSC) into T and B cell-deficient young recipient CD45.2⁺ RAG1^-/- mice, followed by protein-based vaccination.

Results: In the same environment of young RAG1^-/- mice, transplanted DO-HSCs compared to DY-HSCs reconstituted lower numbers of CD19⁺ B cells and CD45.1⁺ cells, though the engraftment of donor-derived HSCs in the young bone marrow (BM) was very similar. Furthermore, indicative for youthful and unchallenged B cell systems, and in contrast to aged mice, very low levels of antigen-experienced memory B cells or age-associated B cells (ABC) developed in both DY-HSC and DO-HSC hosts. The commercially available recombinant SARS-CoV-2 S vaccine (NVX-CoV2373) induced lower IgG⁺ S-antibody titers and pseudovirus neutralization activity in old compared to young mice. In contrast, very similar high IgG⁺ S-antibody titers were induced in DO-HSC and DY-HSC hosts, and pseudovirus neutralization activity was even enhanced in DO-HSC compared with DY-HSC hosts.

Conclusions: Both DO-HSCs and DY-HSCs established in the young recipient BM to a similar extend, suggesting that the concomitant reduction in the de novo reconstitution of CD19⁺ B cells in DO-HSC vs. DY-HSC transplanted animals is specifically related to old HSCs. DO-HSCs and DY-HSCs reconstitute very similar unchallenged B cell systems that efficiently elicit antigen-specific IgG antibodies by protein-based vaccination. Old HSCs thus retain competence to reconstitute a youthful and functional B cell system, at least in the young environment of transplanted RAG1^-/- mice. This suggests that it is primarily age-related factors, and not HSCs per se, that influence the composition and functionality of the old B cell system.

Aging is frequently characterized by an inadequate primary vaccine response, likely due to immunosenescence and inflamm-aging, a low-level, chronic inflammatory state. Both aspects increase the susceptibility of older adults to viral and bacterial infections, resulting in a higher frequency and severity of infectious diseases. In this preliminary study, a cohort of 52 individuals was recruited and divided into two groups: young (age range 21-35) and older adults (> 60 years old). Peripheral blood mononuclear cells (PBMCs) were collected before (time 0, T0) and after (time 1, T1) the immunization with a tetravalent influenza vaccine. Then, T cell immunophenotyping analysis was conducted to investigate how aging and influenza vaccination influence T cell responses. Additionally, the anti-inflammatory and antioxidant effects of oleuropein (OLE), a secoiridoid extracted from extra virgin olive oil, alone or in combination with BIRB 796, a potent inhibitor of p38 MAPK, were explored to enhancing the impact of influenza virus on T cell activation, aiming to identify potential alternatives or complementary strategies to improve traditional flu-vaccine formulations. Statistically significant observations were noted for a decrement in CD8 + T naïve and an increase of effector memory between the young and older adults after flu-vaccination. Moreover, preliminary findings indicate anti-inflammatory and antioxidant properties of OLE and BIRB 796 on T cell responses, particularly regarding Reactive Oxygen Species/Reactive Nitrogen Species modulation, with a trend toward the decrease of pro-inflammatory cytokines (i.e., Interferon-γ (INF-γ), Tumor Necrosis Factor-α (TNF-α)), αalthough without statistical significance.

Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities, making the advanced age as a major predictor of disease severity. Despite this, a comprehensive understanding of the cellular and molecular mechanisms explaining how old age represents a major risk factor remain elusive. To investigate this, we compared SARS-CoV-2 infection outcomes in young adults (2 months) and geriatric (15-22 months) mice. Both groups of K18-ACE2 mice were intranasally infected with 500 TCID₅₀ of SARS-CoV-2 Delta variant with analyses performed on days 3, 5, and 7 post-infection (DPI). Analyses included pulmonary cytokines, lung RNA-seq, viral loads, lipidomic profiles, and histological assessments, with a concurrent evaluation of the percentage of mice reaching humane endpoints. The findings unveiled notable differences, with aged mice exhibiting impaired viral clearance, reduced survival, and failure to recover weight loss due to infection. RNA-seq data suggested greater lung damage and reduced respiratory function in infected aged mice. Additionally, elderly-infected mice exhibited a deficient antiviral response characterized by reduced Th1-associated mediators (IFNγ, CCL2, CCL3, CXCL9) and diminished number of macrophages, NK cells, and T cells. Furthermore, mass-spectrometry analysis of the lung lipidome indicated altered expression of several lipids with immunomodulatory and pro-resolution effects in aged mice such as Resolvin, HOTrEs, and NeuroP, but also DiHOMEs-related ARDS. These findings indicate that aging affects antiviral immunity, leading to prolonged infection, greater lung damage, and poorer clinical outcomes. This underscores the potential efficacy of immunomodulatory treatments for elderly subjects experiencing symptoms of severe COVID-19.

Background: Immunosenescence, the gradual deterioration of the immune system, is critical for aging-related diseases. However, the lack of detailed population-level immune data has limited our understanding, underscoring the need for innovative analytical approaches. The Health and Retirement Study (HRS) in the United States provides a unique opportunity to examine T and B lymphocyte subsets using compositional data analysis and dimension reduction techniques.

Methods: We constructed a hierarchical tree structure to map relationships among T and B subset cells in HRS. Network analysis examined conditional dependence across 16 immune subset cells, while stepwise redundancy analysis (SRDA) identified a subset of pairwise logratio measures that capture main variance in immune composition. We conducted two sets of supervised learning analyses: first, linear penalized log-contrast models to examine the associations between subset cells and three health outcomes (chronic disease index, self-reported health, and frailty level); second, linear regressions to examine the associations between the top selected logratios and health outcomes.

Findings: Our study included 6,250 participants from the HRS with a median age of 68. Network analysis showed some dependence among 16 immune subset cells, including associations between central memory CD4 + T cells and both other CD4 + T cells and other lymphocytes, as well as between central memory CD8 + T cells and other CD8 + T cells. SRDA identified nine key log-ratio measures, explaining over 90% of the variance in immune composition. Linear penalized log-contrast models showed that a lower proportion of naïve CD4 + T cells and higher proportions of other CD4 + and central memory CD8 + T cells were significantly associated with greater chronic disease burden, poorer self-reported health, and higher frailty levels. Linear regression models using log-ratios reinforced these patterns, showing that a higher ratio of other lymphocytes over naïve CD4 + T cells and terminally differentiated effector memory CD4 + T cells over other CD8 + T cells were associated with greater chronic disease burden, poorer self-reported health, and higher frailty levels. In contrast, a higher ratio of other lymphocytes over central memory CD4 + T cells was associated with better health outcomes.

Interpretation: Our findings highlight the value of a systems-based approach and compositional analysis in understanding immunosenescence and its impact on health. The identified subset cells and logratio measures provide meaningful insights into immune aging and warrant further investigation to explore their long-term relationships with health outcomes.

Background: The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2).

Results: Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself.

Conclusions: These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence. Furthermore, these naive T cell signatures could help predict weak vaccine responses, potentially informing targeted vaccination strategies in older adults.

Clinical trial number: EudraCT: 2019-000836-24.

Background: Maintenance of the retina, part of the central nervous system, and other structures in the eye is critical for vision preservation. Aging increases the prevalence of vision impairment, including glaucoma, macular degeneration, and diabetic retinopathy. The retina is primarily maintained by glial cells; however, recent literature suggests that lymphocytes may play a role in the homeostasis of central nervous system tissues. Natural antibodies are produced by B cells without infection or immunization and maintain tissue homeostasis. Here, we explored the potential role of natural immunoglobulin M (IgM) produced by B lymphocytes in maintaining retinal health during aging in mice.

Results: Our results indicate that the vitreous humor of both mice and humans contains IgM and IgG, suggesting that these immunoglobulins may play a role in ocular function. Furthermore, we observed that aged mice lacking secreted IgM (µs-/-) exhibited pronounced retinal degeneration, accompanied by reactive gliosis, and a proinflammatory cytokine environment. This contrasts with the aged wild-type counterparts, which retain their ability to secrete IgM and maintain a better retinal structure and anti-inflammatory environment. In addition to these findings, the absence of secreted IgM was associated with significant alterations in the retinal pigment epithelium, including disruptions to its morphology and signs of increased stress. This was further observed in changes to the blood-retinal-barrier, which is critical for regulation of retinal homeostasis.

Conclusions: These data suggest a previously unrecognized association between a lack of secreted IgM and alterations in the retinal microenvironment, leading to enhanced retinal degeneration during aging. Although the precise mechanism remains unclear, these findings highlight the potential importance of secreted IgM in processes that support retinal health over time. By increasing our understanding of ocular aging, these results show that there is a broader role for the immune system in retinal function and integrity in advanced age, opening new areas for the exploration of immune-related interventions in age-associated retinal conditions.