All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection.

Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy.

Mindfulness-based cognitive therapy in COPD: a cluster randomised controlled trial.

A considerable proportion of patients with chronic obstructive pulmonary disease (COPD) entering pulmonary rehabilitation (PR) report psychological distress, which is often accompanied by poor physical health status. Mindfulness-based cognitive therapy (MBCT) has been shown to improve psychological and physical outcomes in other chronic diseases. We therefore evaluated the efficacy of MBCT as an add-on to a standard PR programme in COPD.COPD patients eligible for PR were cluster randomised to receive either an 8-week, group-based MBCT programme as an add-on to an 8-week PR programme (n=39), or PR alone (n=45). The primary outcomes of psychological distress and physical health status impairment were measured with the Hospital Anxiety and Depression Scale (HADS) and the COPD Assessment Test (CAT) before randomisation (T1), mid- (T2) and post-intervention (T3), and at 3 (T4) and 6 (T5) months' follow-up .A statistically significant time×arm effect was found for the HADS (Cohen's d=0.62, 95% CIs (d)=0.18-1.06, p=0.010). The treatment effect on the CAT failed to reach statistical significance (d=0.42, 95% CIs (d)=-0.06-0.90, p=0.061).MBCT showed a statistically significant and durable effect on psychological distress, indicating that MBCT may be an efficacious add-on to standard PR programmes in COPD.

Candida albicans stimulates IL-23 release by human dendritic cells and downstream IL-17 secretion by Vδ1 T cells.

γδ T cells expressing the Vδ1 TCR are expanded in patients with HIV infection. We show in this article that circulating Vδ1 T cell numbers are particularly high in patients with HIV and candidiasis, and that these cells expand and produce IL-17 in response to Candida albicans in vitro. Although C. albicans could directly stimulate IL-17 production by a subset of Vδ1 T cells, fungus-treated dendritic cells (DCs) were required to expand C. albicans-responsive Vδ1 T cells to generate sufficient numbers of cells to release IL-17 at levels detectable by ELISA. C. albicans induced the release of IL-1ß, IL-6, and IL-23 by DCs, but addition of these cytokines or supernatants of C. albicans-treated DCs to Vδ1 T cells was not sufficient to induce proliferation. We found that direct contact with DCs was required for Vδ1 T cell proliferation, whereas IL-23R-blocking studies showed that IL-23 was required for optimal C. albicans-induced IL-17 production. Because IL-17 affords protection against both HIV and C. albicans, and because Vδ1 T cells are not depleted by HIV, these cells are likely to be an important source of IL-17 in HIV-infected patients with candidiasis, in whom CD4(+) Th17 responses are impaired. These data show that C. albicans stimulates proliferation and IL-17 production by Vδ1 T cells by a mechanism that involves IL-23 release by DCs.

Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vδ3 T cells.

Human γδ T cells expressing the Vδ3 TCR make up a minor lymphocyte subset in blood but are enriched in liver and in patients with some chronic viral infections and leukemias. We analyzed the frequencies, phenotypes, restriction elements, and functions of fresh and expanded peripheral blood Vδ3 T cells. Vδ3 T cells accounted for ~0.2% of circulating T cells, included CD4(+), CD8(+), and CD4(-)CD8(-) subsets, and variably expressed CD56, CD161, HLA-DR, and NKG2D but neither NKG2A nor NKG2C. Vδ3 T cells were sorted and expanded by mitogen stimulation in the presence of IL-2. Expanded Vδ3 T cells recognized CD1d but not CD1a, CD1b, or CD1c. Upon activation, they killed CD1d(+) target cells, released Th1, Th2, and Th17 cytokines, and induced maturation of dendritic cells into APCs. Thus, Vδ3 T cells are glycolipid-reactive T cells with distinct Ag specificities but functional similarities to NKT cells.

Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells.

Alveolar macrophages (AMs) from mice and humans have long been known to contribute to maintaining tolerance in the lung. Studies have shown that AMs can induce anergy in CD4(+) T cells. Nitric oxide, prostaglandins, and leukotrienes have been implicated in AM-mediated tolerance. However, it remains unclear what effect, if any, AMs exert on FoxP3 induction in CD4(+) T cells from mice and humans, and whether or not other immunomodulators might play a role. AMs were isolated from bronchoalveolar lavage (BAL) fluid from either mice or humans, and cocultured with enriched naive CD4(+)FoxP3(-) T cells. We show here for the first time that AMs and AM-conditioned media (AM-CM) from mice and humans induced FoxP3 expression in naive CD4(+) T cells in vitro, an outcome that was reversed in part either by inhibiting retinoic acid (RA) binding to its receptor (RAR), or by blocking transforming growth factor (TGF)-ß1 signaling. A nasal administration of the RAR antagonist reduced the frequencies of CD4(+)FoxP3(+) T cells in the lungs of mice after aerosol challenge with Bordetella pertussis. In addition, we found that the intranasal vaccination of mice with ovalbumin (OVA) protein in conjunction with an RAR inhibitor led to a significant increase in OVA-specific serum IgE. Our findings suggest that AMs can mediate tolerance in the lungs of mice and humans via RA and TGF-ß1. These data may have implications in the development of nasal vaccines in the future.

Psychosocial factors and chronic spontaneous urticaria: a systematic review.

BACKGROUND: Psychosocial factors have been informally associated with Chronic Spontaneous Urticaria (CSU); however, the relationship between psychosocial factors and CSU remains relatively unexplored in the scientific literature. OBJECTIVE: This review aims to provide an evaluation of peer reviewed studies exploring psychosocial factors and CSU. METHODS: A systematic search was performed over four databases identifying studies exploring psychosocial factors in relation to CSU published between the years 1995 and 2022. RESULTS: Eighteen studies were included for narrative analysis, and 33 psychosocial factors were identified. These were split into two subgroups: psychosocial factors that were associated with CSU symptoms aggravation/onset (n = 20), and psychosocial factors expected to be impacted by CSU symptoms (n = 13). CONCLUSION: This review has highlighted a need for more research and interventions to support individuals with psychosocial factors involved in CSU.

Burnout among hospital staff during the COVID-19 pandemic: Longitudinal results from the international Cope-Corona survey study.

OBJECTIVE: Long-term changes in burnout and its predictors in hospital staff during the COVID-19 pandemic were investigated in an international study. METHODS: Two online surveys were distributed to hospital staff in seven countries (Germany, Andorra, Ireland, Spain, Italy, Romania, Iran) between May and October 2020 (T1) and between February and April 2021 (T2), using the following variables: Burnout (emotional exhaustion and depersonalization), job function, age, gender, and contact with COVID-19 patients; individual resources (self-compassion, sense of coherence, social support) and work-related resources and demands (support at the workplace, risk perception, health and safety at the workplace, altruistic acceptance of risk). Data were analyzed using linear mixed models repeated measures, controlled for age. RESULTS: A total of 612 respondents were included (76% women). We found an increase in burnout from T1 to T2. Burnout was high among personnel with high contact with COVID-19 patients. Individual factors (self-compassion, sense of coherence) and work-related factors (support at the workplace, risk perception, health and safety at the workplace) showed associations with burnout. Low health and safety at the workplace at T1 was associated with an increase in emotional exhaustion at T2. Men showed an increase in depersonalization if they had much contact with COVID-19 patients. CONCLUSION: Burnout represents a potential problematic consequence of occupational contact with COVID-19 patients. Special attention should be paid to this group in organizational health management. Self-compassion, sense of coherence, support at the workplace, risk perception, and health and safety at the workplace may be important starting points for interventions. REGISTRATION: Müller, M. M. (2020, August 30). Cope-Corona: Identifying and strengthening personal resources of hospital staff to cope with the Corona pandemic. Open Science Foundation.

The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo.

Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4(+)Foxp3(-) T cell populations, skin CD4(+)Foxp3(+) T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4(+) T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4(+) T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses.

CD11c+CD8alpha+ dendritic cells promote protective immunity to respiratory infection with Bordetella pertussis.

CD11c(+)CD8alpha(+) and CD103(+) dendritic cells (DC) have been shown to promote regulatory T cell responses and mediate tolerance in the gastrointestinal tract. These cells have also been identified in the lung, but their role in immunity to respiratory tract infection is not clear. In this study, we have used a murine model of infection with Bordetella pertussis to examine the function of DC subtypes in protective immunity in the lungs. We found a dramatic increase in the numbers of CD11c(+)CD8alpha(+) DC in the cervical lymph nodes within 4 h of challenge with B. pertussis and these DC could acquire particulate Ag from the upper respiratory tract. CD11c(+)CD8alpha(+) DC also infiltrated the lung with a peak 7 days after B. pertussis challenge. The infiltrating CD11c(+)CD8alpha(+) DC expressed MHC, costimulatory and activation markers indicative of mature DC. The CD11c(+)CD8alpha(+) DC in the cervical lymph nodes expressed IL-4 and IL-10 and lower levels of IFN-gamma, but in the lungs expressed predominantly IFN-gamma. Depletion of CD8alpha(+) cells early in infection attenuated Th1 responses in the lungs and significantly reduced bacterial clearance. Conversely, transfer of FLT3 ligand (FL)-expanded CD11c(+)CD8alpha(+) DC enhanced bacterial clearance, whereas GM-CSF-expanded conventional DC had no effect. The numbers of CD11c(+)CD8alpha(+)CD103(+) cells were also increased during the early phase of infection. Blocking CD103 function caused a significant delay in bacterial clearance and a reduction in cellular infiltration into the lungs. These findings demonstrate that CD11c(+)CD8alpha(+) and CD11c(+)CD103(+)DC play a protective role in mediating immunity to B. pertussis infection in the respiratory tract.

Feasibility assessment of an 8-week attention-based training programme in the management of chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria is a common disorder that is poorly understood and frequently misdiagnosed. Psychological difficulties are a significant factor in dermatological diseases and may also aggravate symptom burden. Mind-body interventions are used as a complementary approach to alleviate symptoms in chronic diseases and may represent a valuable non-pharmacological approach in CSU. METHODS: We sought to develop and evaluate the feasibility of an 8-week attention-based training (ABT) programme, coupled to biofeedback technology for CSU. Through convergent interviews, we gathered information from individuals with urticaria about possible links between stress, mood and skin symptoms. Using these data, we recruited 12 participants to engage in an amended ABT programme for patients with CSU, comprising eight 90-min sessions held weekly. Participants completed psychometric measures and measures of urticaria symptomatology as assessed by the urticaria control test, prior to and after the intervention. Adherence to ABT practice was measured using individual inner balance devices which tracked heart rate variability. We completed qualitative interviews after the intervention to obtain feedback on participant experience of the programme. RESULTS: Participants with CSU described how their psychological wellbeing can be linked to skin symptoms, poor sleep and difficulty concentrating. An amended ABT programme was found to be an acceptable component of care in the management of CSU. Retention of participants in the programme was challenging with 33% participants dropping out of the programme. For those who did complete the programme, three participants exceeded weekly practice at week 8. A decrease in severity of urticaria symptomatology as measured by the urticaria control test was observed upon completion of the intervention. The most commonly cited barrier to implementation of the programme was the time commitment required. CONCLUSIONS: Integrating an ABT programme into routine clinical care for CSU patients is feasible and was deemed acceptable and valuable by individuals who took part. Further formal evaluation of ABT for CSU including the analysis of biochemical parameters is required to determine its role in the management of this distressing condition. TRIAL REGISTRATION: This trial is registered with ISRCTN with study ID ISRCTN13672947 . Registration took place on 22/09/2020 (retrospectively registered).

Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1ß, and T Helper Cell Responses to Mycobacterium tuberculosis.

Tuberculosis (TB) is the leading infectious killer in the world. Mycobacterium tuberculosis (Mtb), the bacteria that causes the disease, is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung. Infected macrophages then upregulate effector functions through epigenetic modifications to make DNA accessible for transcription. The metabolic switch to glycolysis and the production of proinflammatory cytokines are key effector functions, governed by epigenetic changes, that are integral to the ability of the macrophage to mount an effective immune response against Mtb. We hypothesised that suberanilohydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor (HDACi), can modulate epigenetic changes upstream of the metabolic switch and support immune responses during Mtb infection. The rate of glycolysis in human MDM, infected with Mtb and treated with SAHA, was tracked in real time on the Seahorse XFe24 Analyzer. SAHA promoted glycolysis early in the response to Mtb. This was associated with significantly increased production of IL-1ß and significantly reduced IL-10 in human MDM and AM. Since innate immune function directs downstream adaptive immune responses, we used SAHA-treated Mtb-infected AM or MDM in a co-culture system to stimulate T cells. Mtb-infected macrophages that had previously been treated with SAHA promoted IFN-γ, GM-CSF, and TNF co-production in responding T helper cells but did not affect cytotoxic T cells. These results indicate that SAHA promoted the early switch to glycolysis, increased IL-1ß, and reduced IL-10 production in human macrophages infected with Mtb. Moreover, the elevated proinflammatory function of SAHA-treated macrophages resulted in enhanced T helper cell cytokine polyfunctionality. These data provide an in vitro proof-of-concept for the use of HDACi to modulate human immunometabolic processes in macrophages to promote innate and subsequent adaptive proinflammatory responses.

Burnout in the emergency department: Randomized controlled trial of an attention-based training program.

BACKGROUND: Burnout (encompassing emotional exhaustion, depersonalization and personal accomplishment) in healthcare professionals is a major issue worldwide. Emergency medicine physicians are particularly affected, potentially impacting on quality of care and attrition from the specialty. OBJECTIVE: The aim of this study was to apply an attention-based training (ABT) program to reduce burnout among emergency multidisciplinary team (MDT) members from a large urban hospital. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Emergency MDT members were randomized to either a no-treatment control or an intervention group. Intervention group participants engaged in a four session (4 h/session) ABT program over 7 weeks with a practice target of 20 min twice-daily. Practice adherence was measured using a smart phone application together with a wearable Charge 2 device. MAIN OUTCOME MEASURES: The primary outcome was a change in burnout, comprising emotional exhaustion, depersonalization and personal achievement. The secondary outcomes were changes in other psychological and biometric parameters. RESULTS: The ABT program resulted in a significant reduction (P < 0.05; T1 [one week before intervention] vs T3 [follow-up at two months after intervention]) in burnout, specifically, emotional exhaustion, with an effect size (probability of superiority) of 59%. Similar reductions were observed for stress (P < 0.05) and anxiety (P < 0.05). Furthermore, ABT group participants demonstrated significant improvements in heart rate variability, resting heart rate, sleep as well as an increase in pro-inflammatory cytokine expression. CONCLUSION: This study describes a positive impact of ABT on emergency department staff burnout compared to a no-treatment control group. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02887300.

Mantra meditation programme for emergency department staff: a qualitative study.

OBJECTIVES: Rates of burnout and stress in healthcare practitioners are steadily increasing. Emergency department (ED) staff are particularly susceptible to such poor outcomes. Mantra meditation (MM) may contribute to increased well-being. The primary aim of this study was to obtain indepth qualitative feedback on ED staff's experience of a MM programme. A secondary objective was to harness staff's perception of the ED working environment. DESIGN: Qualitative study. SETTING: ED in St James' Hospital, Dublin, Ireland. PARTICIPANTS: Doctors, nurses, allied health professionals and administrative staff (n=10, eight women, mean age 35.6 years) working in the ED who attended a MM programme. METHODS: Semistructured interviews were conducted by a trained independent researcher. Interviews were transcribed and thematically analysed. RESULTS: Five main themes and six subthemes were identified: work pressure and perceived stress; perceived benefits of meditation (with subthemes of increased attention/awareness, improved emotion regulation and new coping mechanisms, relaxation and sleep quality); conflicting attitudes to practice; barriers to meditation practice (with subthemes of schedule, length of practice and individual differences); and facilitators to practice. CONCLUSION: ED staff in this study described the demands of their work and voiced a need for a workplace well-being programme. Our findings suggest that MM might represent a viable tool to develop attention and awareness, improve emotion regulation and improve their capacity to cope with stress, which may impact their workplace well-being, wider health service, patient safety and quality of care. Support from the organisation is considered to be integral to embedding of a workplace well-being programme, such as the practice of meditation into their daily lives.

CD3ε Expression Defines Functionally Distinct Subsets of Vδ1 T Cells in Patients With Human Immunodeficiency Virus Infection.

Human γδ T cells expressing the Vδ1 T cell receptor (TCR) recognize self and microbial antigens and stress-inducible molecules in a major histocompatibility complex-unrestricted manner and are an important source of innate interleukin (IL)-17. Vδ1 T cells are expanded in the circulation and intestines of patients with human immunodeficiency virus (HIV) infection. In this study, we show that patients with HIV have elevated frequencies, but not absolute numbers, of circulating Vδ1 T cells compared to control subjects. This increase was most striking in the patients with Candida albicans co-infection. Using flow cytometry and confocal microscopy, we identify two populations of Vδ1 T cells, based on low and high expression of the ε chain of the CD3 protein complex responsible for transducing TCR-mediated signals (denoted CD3εlo and CD3εhi Vδ1 T cells). Both Vδ1 T cell populations expressed the CD3 ζ-chain, also used for TCR signaling. Using lines of Vδ1 T cells generated from healthy donors, we show that CD3ε can be transiently downregulated by activation but that its expression is restored over time in culture in the presence of exogenous IL-2. Compared to CD3εhi Vδ1 T cells, CD3εlo Vδ1 T cells more frequently expressed terminally differentiated phenotypes and the negative regulator of T cell activation, programmed death-1 (PD-1), but not lymphocyte-activation gene 3, and upon stimulation in vitro, only the CD3εhi subset of Vδ1 T cells, produced IL-17. Thus, while HIV can infect and kill IL-17-producing CD4+ T cells, Vδ1 T cells are another source of IL-17, but many of them exist in a state of exhaustion, mediated either by the induction of PD-1 or by downregulation of CD3ε expression.

Therapeutic use of vitamin D and its analogues in autoimmunity.

In recent years, there has been great interest in the role of vitamin D in a number of diverse human diseases including autoimmunity, allergy, infection, cardiovascular disease, chronic lung disease, transplantation and cancer. Vitamin D is best known for its role in calcium metabolism; however it also has potent immunomodulatory effects. Epidemiological studies suggest that vitamin D deficiency may be a significant risk factor for many diseases. Furthermore, there is accumulating evidence from experimental studies that vitamin D has anti-inflammatory effects. Recent studies have indicated that a surprisingly high proportion of people are vitamin D deficient, suggesting that vitamin D supplementation may be of benefit to human health. This review will focus on the role of vitamin D in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and diabetes. We will review the epidemiological and experimental evidence for the protective effects of vitamin D in autoimmunity, as well as the preliminary vitamin D intervention studies and the most recent patented vitamin D analogues.

The immunoregulatory role of CD4⁺ FoxP3⁺ CD25⁻ regulatory T cells in lungs of mice infected with Bordetella pertussis.

The identification of regulatory T (Treg) cells was originally based on CD25 expression; however, CD25 is also expressed by activated effector T cells. FoxP3 is a more definitive marker of Treg cells, and CD4(+) FoxP3(+) CD25(+) T cells are considered the dominant natural Treg (nTreg) population. It has been suggested that certain CD4(+) FoxP3(+) Treg cells do not express CD25. In this study, we used a murine model of respiratory infection with Bordetella pertussis to examine the role of Treg cells in protective immunity in the lung. We first demonstrated that CD4(+) FoxP3(+) CD25(-) cells are the dominant Treg population in the lung, gut and liver. Pre-activated lung CD4(+) FoxP3(+) CD25(-) cells suppressed CD4(+) effector T cells in vitro, which was partly mediated by IL-10 and not dependent on cell contact. Furthermore, CD4(+) FoxP3(+) CD25(-) IL-10(+) T cells were found in the lungs of mice at the peak of infection with B. pertussis. The rate of bacterial clearance was not affected by depletion of CD25(+) cells or in IL-10-deficient (IL-10(-/-) ) mice, but was compromised in CD25-depleted IL-10(-/-) mice. Our findings suggest that IL-10-producing CD4(+) FoxP3(+) CD25(-) T cells represent an important regulatory cell in the lung.

Recent advances in regulatory T cell therapy of autoimmunity, graft rejection and cancer.

Since their initial discovery in the 1970s and their subsequent resurgence in the mid 1990s, regulatory T (Treg) cells have become one of the most studied cell subsets. Treg cells prevent autoimmunity and limit aggressive immune responses directed against either pathogen or foreign antigen that might serve to damage host tissue. In contrast, tumour cells have been shown to recruit and/or induce Treg cells, which can impair tumour immunity. The immunoregulatory function of these cells makes them ideal therapeutic candidates for the treatment of autoimmune disease and in the prevention of transplant rejection. Likewise, depletion of Treg cells remains an additional option in the treatment of cancer. Despite significant advances in the treatment of murine models of disease with Treg cells, it has been difficult to transfer this success into the clinic. In this review, we will discuss relevant patents and the most recent advances in the use of Treg cells to treat autoimmunity, prevent graft rejection as well as the use of antibodies to deplete these cells in cancer.