Jane Upton

An age-related numerical and functional deficit in CD19 + CD24 hi CD38 hi B cells is associated with an increase in systemic autoimmunity

Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19+CD24hiCD38hi phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19+CD24hiCD38hi cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll‐like receptors was also impaired in CD19+CD24hiCD38hi B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19+CD24hiCD38hi B‐cell function was compromised by age‐related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19+CD24hiCD38hi B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age‐associated change in expression of costimulatory molecules CD80 and CD86 on CD19+CD24hiCD38hi cells, suggesting IL10‐dependent immune suppression is impaired, but contact‐dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19+CD24hiCD38hi B‐cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age‐related decline in CD19+CD24hiCD38hi B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.

Depression following hip fracture is associated with increased physical frailty in older adults: the role of the cortisol: dehydroepiandrosterone sulphate ratio

BackgroundHip fracture in older adults is associated with depression and frailty. This study examined the synergistic effects of depression and hip fracture on physical frailty, and the mediating role of the cortisol:dehydroepiandrosterone sulphate (DHEAS) ratio.MethodsThis was an observational longitudinal study of patients with a hip fracture carried out in a hospital setting and with follow up in the community.Participants were 101 patients aged 60+ years (81 female) with a fractured neck of femur.Measurements of the ability to carry out activities of daily living (ADL), cognitive function, physical frailty and assays for serum cortisol and DHEAS were performed six weeks and six months post-hip fracture. Depressed and non-depressed groups were compared by ANOVA at each time point.ResultsHip fracture patients who developed depression by week six (n = 38) had significantly poorer scores on ADL and walking indices of frailty at both week six and month six, and poorer balance at week six. The association with slower walking speed was mediated by a higher cortisol:DHEAS ratio in the depressed group.ConclusionDepression following hip fracture is associated with greater physical frailty and poorer long term recovery post-injury. Our data indicate that the underlying mechanisms may include an increased cortisol:DHEAS ratio and suggest that correcting this ratio for example with DHEA supplementation could benefit this patient population.

Depressive symptoms are associated with reduced neutrophil function in hip fracture patients.

Highlight • Depressive symptoms are a major driver of reduced immunity after hip fracture.

Depressive symptoms in hip fracture patients are associated with reduced monocyte superoxide production.

Ageing is accompanied by reduced functioning of the immune system, termed immunesenescence which is associated with increased risk of infection and mortality. However the immune system does not operate in isolation and can be modified by many environmental factors, including stress. In this study we determined whether physical stress (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system, specifically on monocyte numbers and function. We assessed immune function in 101 hip fracture patients (81 female) 6weeks and 6months after injury and 43 healthy age matched controls (28 females). Thirty-eight of the hip fracture group were found to be depressed at the 6week sampling. No differences in peripheral monocyte count, distribution of monocyte subsets or TNFα secretion were observed between hip fracture patients and healthy controls. However we observed significantly reduced superoxide production in response to Escherichia coli in the monocytes of hip fracture patients who developed depressive symptoms compared with non-depressed hip fracture patients (p=0.002) or healthy controls (p=0.008) 6weeks after the fracture which remained decreased 6months following injury. In previous studies we have shown an effect of depression on neutrophil superoxide generation in hip fracture patients, suggesting a particular susceptibility of this aspect of immune cell function to psychological stress.

Correlation between perceived asthma control and thoraco-abdominal asynchrony in primary care patients diagnosed with asthma.

Objective. Thoraco-abdominal asynchrony (TAA), the discordant movement of the abdomen and thorax, may impact upon health-related variables. Here, we investigated the extent to which TAA is associated with health-related variables, particularly perceived asthma control and quality of life. Methods. Ambulatory respiratory data from 43 patients diagnosed with asthma and 43 healthy age and sex-matched controls were recorded over 4 hours. Phase relation (Ph Rel Total), the percentage of time that the effects of rib cage (RC) and diaphragmatic movement result in opposite effects on intra-thoracic volume, quantified TAA. Subjects completed the Mini Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ), Nijmegen questionnaire (NQ), Hospital Anxiety and Depression Scale (HADS), Spielberger State-Trait Anxiety Inventory (STAI), and General Health Perception (GHP) subscale of the short form 36 questionnaire’. Capnography profiling, breath-hold time (BHT), and standard spirometry were performed. Results. The time in asynchrony was significantly greater in the asthma than in the healthy control group (Ph Rel Total = 14% (interquartile range (IQR) 8.5–20.7%) versus 10.4% (IQR 7.1–14.5%), p = .012). In patients with asthma, Ph Rel Total was weakly associated with poorer ACQ scores (r = 0.33, p = .03), and in the healthy control group with GHP (r = 0.319, p = .037). Post-hoc exploratory analysis revealed a moderate relationship in the female asthma subgroup between Ph Rel Total and AQLQ (r = −0.56, p = .003). Conclusions. TAA may be associated with decreased perceived asthma control. In healthy individuals, asynchrony may be associated with low perception of general health. Further studies are required to investigate if the reduction of TAA improves these health-related variables.

Asthma-specific health-related quality of life of people in Great Britain: A national survey

Abstract Background: Although the ultimate goal of asthma treatment is to improve asthma-specific Health-Related Quality-Of-Life (HRQOL), in the UK population this is insufficiently studied. National asthma-specific HRQOL data is needed to inform strategies to address this condition. Aims and objectives: To benchmark asthma-specific HRQOL in a national survey of adults with asthma, and explore differences in this measure within subsections of the population. Methods: We analysed answers to the Marks Asthma Quality-of-Life Questionnaire (AQLQ-M) from a representative sample of 658 adults with asthma. Respondents answered asthma-specific questions to assess control, previous hospital admissions, asthma attacks and an indicator of severity. Higher scores indicate poorer HRQOL (maximum = 60). The highest quintile formed a subgroup ‘Poor HRQOL’. Data were weighted to correct for any biases caused by differential non-response. Chi-square analyses were used to determine differences between good and poor quality of life and regression analyses performed to determine what factors are associated with poor HRQOL. Results: The response rate was 49%. AQLQ-M median (IQR) scores were 5 (2–13) for the total sample (poor HRQOL = 21, good HRQOL = 3). Significant differences between good and poor HRQOL were observed in smoking status, SES, employment status and co-morbidities, but no differences were found between age groups. Those with poorly controlled asthma were significantly more likely to have poor HRQOL, ≥1 breathing related hospital admission or ≥1 asthma attack. Conclusions: This article provides benchmarking data on asthma-specific HRQOL. Improved strategies are needed to target interventions towards people experiencing poor HRQOL.

New-Onset Depression Following Hip Fracture Is Associated With Increased Length of Stay in Hospital and Rehabilitation Centers

This article examines the coincident effects of new-onset depression post hip fracture on length of hospital stay, readmission rates, and incidence of infections in older adults. Participants were 101 hip fracture patients aged 60+ years; 38 developed depressive symptoms following their fracture. Infection rates, readmissions to hospital and rehabilitation units, and length of hospital stay were assessed over the 6 months post hip fracture from hospital and general practitioner notes. Patients who developed depression by Week 6 post fracture were likely to spend more time in hospital/rehabilitation wards (p = .02) and more likely to be discharged to a rehabilitation unit (p < .05). There were no group differences in readmissions or infection rates. New-onset depression coincident with hip fracture in older adults is associated with longer hospital ward stays and greater need for rehabilitation.

Stress and Ageing: Effects on Neutrophil Function

The innate or non-specific immune system consists of soluble components, namely the complement system and cellular elements. The latter includes neutrophils, which make up the majority of the innate immune cells in circulation, and deal with rapidly dividing bacteria. This chapter will focus on the influence of psychological stress and ageing on neutrophil numbers and function. Neutrophils are a major component of innate immunity and are the dominant leukocyte in the circulation, making up 60 % of the white cell count. They are also the shortest lived blood cell, dying by apoptosis approximately 24 h after leaving the bone marrow (Savill et al., J Clin Invest 83:865–875, 1989; Scheel-Toellner et al , Biochem Soc Trans 32:461–464, 2004). These cells play a crucial role in killing invading pathogens, particularly rapidly dividing bacteria, and are key cellular components of the early phase of inflammatory responses (Nathan et al., Nat Rev Immunol 6:173–182, 2006). Neutrophils act quickly and without specificity, although their bacterial recognition systems are many and complex. Neutrophils are recruited to sites of infection via chemical homing (chemotactic) signals, such as the chemokine CXCL8 (also known as IL8). Once in contact with the pathogen they uptake the microbe by engulfing (phagocytosis) mediated via opsonic receptors that detect complement proteins C3b and C3Bi or antibody coating the microbe.