Control of immune cell trafficking through inter-organ communication.

Cell migration is a cardinal feature of the immune system. Immune cell trafficking is orchestrated principally by chemokines and adhesion molecules, which guide the cells to the right place and at the right time to efficiently induce immune responses. Recent studies have demonstrated that signals from other organ systems influence the expression of and responsiveness to these guidance cues and consequentially immune cell migration. Neuronal inputs control entry and exit of immune cells to and from lymphoid and non-lymphoid tissues. The circadian clock helps establish diurnal variations in immune cell distribution among tissues. Nutritional status also alters immune cell homing to the bone marrow. In this review, we summarize the current knowledge about inter-organ control of immune cell trafficking and discuss the physiological and pathological significance of these mechanisms.

Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol.

BACKGROUND: There is increasing recognition of the substantial burden of mental health disorders at an individual and population level, including consequent demand on mental health services. Lifestyle-based mental healthcare offers an additional approach to existing services with potential to help alleviate system burden. Despite the latest Royal Australian New Zealand College of Psychiatrists guidelines recommending that lifestyle is a 'first-line', 'non-negotiable' treatment for mood disorders, few such programs exist within clinical practice. Additionally, there are limited data to determine whether lifestyle approaches are equivalent to established treatments. Using an individually randomised group treatment design, we aim to address this gap by evaluating an integrated lifestyle program (CALM) compared to an established therapy (psychotherapy), both delivered via telehealth. It is hypothesised that the CALM program will not be inferior to psychotherapy with respect to depressive symptoms at 8 weeks. METHODS: The study is being conducted in partnership with Barwon Health's Mental Health, Drugs & Alcohol Service (Geelong, Victoria), from which 184 participants from its service and surrounding regions are being recruited. Eligible participants with elevated psychological distress are being randomised to CALM or psychotherapy. Each takes a trans-diagnostic approach, and comprises four weekly (weeks 1-4) and two fortnightly (weeks 6 and 8) 90-min, group-based sessions delivered via Zoom (digital video conferencing platform). CALM focuses on enhancing knowledge, behavioural skills and support for improving dietary and physical activity behaviours, delivered by an Accredited Exercise Physiologist and Accredited Practising Dietitian. Psychotherapy uses cognitive behavioural therapy (CBT) delivered by a Psychologist or Clinical Psychologist, and Provisional Psychologist. Data collection occurs at baseline and 8 weeks. The primary outcome is depressive symptoms (assessed via the Patient Health Questionnaire-9) at 8 weeks. Societal and healthcare costs will be estimated to determine the cost-effectiveness of the CALM program. A process evaluation will determine its reach, adoption, implementation and maintenance. DISCUSSION: If the CALM program is non-inferior to psychotherapy, this study will provide the first evidence to support lifestyle-based mental healthcare as an additional care model to support individuals experiencing psychological distress. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12621000387820 , Registered 8 April 2021.

Associations Between Muscle Quality and Cognitive Function in Older Men: Cross-Sectional Data From the Geelong Osteoporosis Study.

Sarcopenia-related declines appear to be adversely associated with cognition in the elderly. Poor muscle quality is a marker for sarcopenia, yet little research has examined the concurrence of poor muscle quality and poor cognition. The aim of this study was to investigate the association between muscle quality and cognitive function, overall and in specific domains, in older men. This study involved 342 men from the Geelong Osteoporosis Study (ages 60-96 years). Handgrip strength (HGS, kg) was measured by dynamometry (Vernier, LoggerPro3), and lean mass of arms (kg) and appendicular lean mass (ALM, kg) by dual-energy X-ray absorptiometry (Lunar). Muscle quality was expressed as HGS/(arm lean mass) (kg/kg) as well as HGS/ALM (kg/kg). Cognitive function was assessed in 4 domains: visual attention, psychomotor function, working memory and visual learning. Overall cognitive function scores were calculated. Higher scores represent poorer cognitive performance in attention, psychomotor function and working memory, but better performance for visual memory/learning and overall cognitive function. Additionally, cognitive impairment was determined by the mini-mental state exam (score ≤ 24). Linear regression analyses and logistic regression were performed. There were age-related declines observed for all measures relating to muscle and cognition. Muscle quality (HGS/arm lean mass) was associated with all cognition assessments before and after adjusting for age, except for age-adjusted working memory. Muscle quality (HGS/arm lean mass) was associated with psychomotor function (B -0.01, 95% CI -0.02, -0.005) and overall cognitive function (b + 0.07, 95% CI 0.03, 0.11) after adjusting for age and education. Greater muscle quality was also associated with the likelihood of cognitive impairment OR 0.64 (95%CI 0.46-0.88) after adjusting for age; associations with attention and visual memory/learning were attenuated after further adjustment for confounders. Similar patterns were observed when muscle quality was determined as HGS/ALM. Our data support an association between muscle quality and cognitive function. Further research is needed to examine temporal changes between the Two.

Skeletal Muscle Density and Cognitive Function: A Cross-Sectional Study in Men.

We aimed to investigate cross-sectional associations between skeletal muscle density, a proxy measure for fatty infiltration into muscle, and cognition. Contributions from body fat mass, systemic inflammation and lifestyle were explored, as these factors have been identified in both muscle and cognitive deterioration. For 281 men (60-95 year) from the Geelong Osteoporosis Study, radial and tibial muscle density were measured using peripheral quantitative computed tomography. Body fat and appendicular lean mass were measured using dual-energy X-ray absorptiometry. Cognitive function was assessed for psychomotor function (DET), visual identification/attention (IDN), visual learning (OCL) and working memory (OBK) (CogState Brief Battery). Composite scores signified overall cognitive function (OCF). Higher scores represent poorer performance except for OCL and OCF. Regression analyses examined associations between muscle density and cognition; potential confounders included age, muscle cross-sectional area (CSA), body composition, lifestyle and serum markers of inflammation. Negative associations with age were evident for muscle density, all cognitive domains and OCF. Muscle density at both sites was positively associated with DET, OCL and OCF. After adjustment for age, the association persisted for DET (radius: B = - 0.006, p = 0.02; tibia: B = - 0.003, p = 0.04) and OCL (radius B = + 0.004, p = 0.02; tibia: B = + 0.005, p < 0.001). At the radius, further adjustment for serum TNF-α explained the association between muscle density (B = - 0.002, p = 0.66) and DET. Education and physical activity contributed to the model for radial muscle density and DET. There were no contributions from muscle CSA, appendicular lean mass, body fat mass, other markers of inflammation or other potential confounders. At the tibia, the association between muscle density and DET (B = - 0.003, p = 0.04) was independent of TNF-α. There was an age-adjusted association between muscle density and OCL at both sites (radius: B = + 0.004, p = 0.02; tibia: B = + 0.005, p < 0.001). None of the potential confounders contributed to the models. Muscle density was associated with cognitive function in the DET and OCL domains. However, there was little evidence that this was explained by inflammation or body fat mass. No associations were identified between muscle density and IDN or OBK.

Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection.

While two memory compartments, memory B cells and long-lived plasma cells, are thought to contribute to the successful establishment of memory recall responses, the unique roles of each cellular compartment are still unclear. Herein, by tracing influenza anti-hemagglutinin (HA)-specific antibodies in mice, we demonstrate that pre-existing antibodies secreted by long-lived plasma cells are essential for protection from reinfection with the same influenza virus, whereas protection from secondary infection with an antigenically distinct influenza virus requires memory B-cell activation. These activated memory B cells were largely specific for the conserved HA stem region, and generated sufficient levels of antibodies for protection from heterologous reinfection. Given that the anti-stem plasmablasts derived from the memory B cells were higher affinity than those from naive B cells, our results suggest that maturation of anti-stem memory B cells during primary influenza infection and their subsequent activation are required for protection from reinfection by mutant viruses.

Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells.

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remain unclear. We report that, although surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACI(+) transitional cells from BAFF-transgenic mice are characterized by an activated, cycling phenotype, and the TACI(+) cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase and T-bet, and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACI(+) transitional B cells from BAFF-transgenic mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism through which BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.

Zika virus dumbbell-1 structure is critical for sfRNA presence and cytopathic effect during infection.

All flaviviruses contain conserved RNA structures in the 3' untranslated region (3' UTR) that are important for flavivirus RNA replication, translation, and pathogenesis. Flaviviruses like Zika virus (ZIKV) contain multiple conserved RNA structures in the viral 3' UTR, including the structure known as dumbbell-1 (DB-1). Previous research has shown that the DB-1 structure is important for flavivirus positive-strand genome replication, but the functional role of the flavivirus DB-1 structure and the mechanism by which it contributes to viral pathogenesis are not known. Using the recently solved flavivirus DB RNA structural data, we designed two DB-1 mutant ZIKV infectious clones, termed ZIKV-TL.PK and ZIKV-p.2.5', which disrupt DB-1 tertiary folding. We found that viral positive-strand genome replication of both ZIKV DB-1 mutant clones is similar to wild-type (WT) ZIKV, but ZIKV DB-1 mutants exhibit significantly decreased cytopathic effect due to reduced caspase-3 activation. We next show that ZIKV DB-1 mutants exhibit decreased levels of sfRNA species compared to ZIKV-WT during infection. However, ZIKV DB-1 mutant 3' UTRs exhibit unchanged sfRNA biogenesis following XRN1 degradation in vitro. We also found that ZIKV DB-1 mutant virus (ZIKV-p.2.5') exhibited enhanced sensitivity to type I interferon treatment, and both ZIKV-DB-1 mutants exhibit reduced morbidity and mortality due to tissue-specific attenuated viral replication in brain tissue of interferon type I/II receptor knockout mice. We propose that the flavivirus DB-1 RNA structure maintains sfRNA levels during infection despite maintained sfRNA biogenesis, and these results indicate that ZIKV DB-dependent maintenance of sfRNA levels support caspase-3-dependent, cytopathic effect, type I interferon resistance, and viral pathogenesis in mammalian cells and in a ZIKV murine model of disease. IMPORTANCE The group of viruses termed flaviviruses cause important disease throughout the world and include dengue virus, Zika virus, Japanese encephalitis virus, and many more. All of these flaviviruses have highly conserved RNA structures in the untranslated regions of the virus genome. One of the shared RNA structures, termed the dumbbell region, is not well studied, but mutations in this region are important for vaccine development. In this study, we made structure-informed targeted mutations in the Zika virus dumbbell region and studied the effect on the virus. We found that Zika virus dumbbell mutants are significantly weakened or attenuated due to a decreased ability to produce non-coding RNA that is needed to support infection, support virus-induced cell death, and support escape from the host immune system. These data show that targeted mutations in the flavivirus dumbbell RNA structure may be an important approach to develop future vaccine candidates.

Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex.

Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.

Prevalence of Sarcopenia Employing Population-Specific Cut-Points: Cross-Sectional Data from the Geelong Osteoporosis Study, Australia.

BACKGROUND: Prevalence estimates for sarcopenia vary depending on the ascertainment criteria and thresholds applied. We aimed to estimate the prevalence of sarcopenia using two international definitions but employing Australian population-specific cut-points. METHODS: Participants (n = 665; 323 women) aged 60-96 years old were from the Geelong Osteoporosis Study. Handgrip strength (HGS) was measured by dynamometers and appendicular lean mass (ALM) by whole-body dual-energy X-ray absorptiometry. Physical performance was assessed using gait speed (GS, men only) and/or the timed up-and-go (TUG) test. Using cut-points equivalent to two standard deviations (SDs) below the mean young reference range from the same population and recommendations from the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia was identified by low ALM/height2 (<5.30 kg for women; <6.94 kg for men) + low HGS (<16 kg women; <31 kg men); low ALM/height2 + slow TUG (>9.3 s); low ALM/height2 + slow GS (<0.8 m/s). For the Foundation for the National Institutes of Health (FNIH) equivalent, sarcopenia was identified as low ALM/BMI (<0.512 m2 women, <0.827 m2 men) + low HGS (<16 kg women, <31 kg men). Receiver Operating Characteristic curves were also applied to determine optimal cut-points for ALM/BMI (<0.579 m2 women, <0.913 m2 men) that discriminated poor physical performance. Prevalence estimates were standardized to the Australian population and compared to estimates using international thresholds. RESULTS: Using population-specific cut-points and low ALM/height2 + HGS, point-estimates for sarcopenia prevalence were 0.9% for women and 2.9% for men. Using ALM/height2 + TUG, prevalence was 2.5% for women and 4.1% for men, and using ALM/height2 + GS, sarcopenia was identified for 1.6% of men. Using ALM/BMI + HGS, prevalence estimates were 5.5-10.4% for women and 11.6-18.4% for men. CONCLUSIONS: This study highlights the range of prevalence estimates that result from employing different criteria for sarcopenia. While population-specific criteria could be pertinent for some populations, a consensus is needed to identify which deficits in skeletal muscle health are important for establishing an operational definition for sarcopenia.

Adrenergic Signaling in Circadian Control of Immunity.

Circadian rhythms govern a multitude of physiologic processes, both on a cell-intrinsic level and systemically, through the coordinated function of multi-organ biosystems. One such system-the adrenergic system-relies on the catecholamine neurotransmitters, adrenaline and noradrenaline, to carry out a range of biological functions. Production of these catecholamines is under dual regulation by both neural components of the sympathetic nervous system and hormonal mechanisms involving the hypothalamus-pituitary-adrenal axis. Importantly, both neural and hormonal arms receive input from the body's central clock, giving rise to the observed rhythmic variations in catecholamine levels in blood and peripheral tissues. Oscillations in catecholamine signals have the potential to influence various cellular targets expressing adrenergic receptors, including cells of the immune system. This review will focus on ways in which the body's central master clock regulates the adrenergic system to generate circadian rhythms in adrenaline and noradrenaline, and will summarize the existing literature linking circadian control of the adrenergic system to immunologic outcomes. A better understanding of the complex, multi-system pathways involved in the control of adrenergic signals may provide immunologists with new insight into mechanisms of immune regulation and precipitate the discovery of new therapeutics.

Muscle strength and gait speed rather than lean mass are better indicators for poor cognitive function in older men.

We aimed to examine muscle strength, function and mass in relation to cognition in older men. This cross-sectional data-set included 292 men aged ≥60 yr. Handgrip strength (kg) was measured by dynamometry, gait speed by 4-metre walk (m/s) and appendicular lean mass (kg) by dual-energy x-ray absorptiometry. Cognition was assessed across four domains: psychomotor function, attention, visual learning and working memory. Composite scores for overall cognition were calculated. Bivariate analyses indicated that handgrip strength and gait speed were positively associated with cognitive function. After accounting for confounders, positive associations between individual muscle (or physical) measures and cognitive performance were sustained for handgrip strength and psychomotor function, gait speed and psychomotor function, gait speed and attention, handgrip strength and overall cognition, and gait speed and overall cognition. In multivariable models, handgrip strength and gait speed independently predicted psychomotor function and overall cognition. No associations were detected between lean mass and cognition after adjusting for confounders. Thus, low muscle strength and slower gait speed, rather than low lean mass, were associated with poor cognition in older men.

Handgrip strength and muscle quality in Australian women: cross-sectional data from the Geelong Osteoporosis Study.

BACKGROUND: Low handgrip strength (HGS) is a measure of poor skeletal muscle performance and a marker of ill health and frailty. Muscle quality (MQ) is a measure of muscle strength relative to muscle mass. We aimed to develop normative data for HGS and MQ, report age-related prevalence of low HGS and MQ, and determine the relationship with age, anthropometry, and body composition for women in Australia. METHODS: This cross-sectional analysis included data from 792 women (ages 28-95 years) assessed by the Geelong Osteoporosis Study. Duplicate measures of HGS were performed for each hand with a dynamometer (Jamar) and the mean of maximum values used for analyses. Dual energy X-ray absorptiometry-derived lean mass for the arms was used to calculate MQ as HGS/lean mass (kg/kg). Body mass index (BMI) was categorized as normal (BMI < 25.0 kg/m2 ), overweight (25.0-29.9 kg/m2 ), and obese (>30.0 kg/m2 ). Fat mass index (FMI) was calculated as whole body fat/height2 (kg/m2 ) and appendicular lean mass index (ALMI) as lean mass of arms and legs/height2 (kg/m2 ). RESULTS: Mean (±SD) of HGS values for normal BMI, overweight, and obese groups were 25 (±7), 24 (±7), and 24 (±7) kg, P = 0.09, and for MQ, 12 (±3), 11 (±3), and 10 (±3) kg/kg, P < 0.001. Our data indicated a quadratic relationship between age and HGS or MQ. Mean HGS and MQ remained stable until the fifth age decade then declined steadily with increasing age; therefore, we used data for women (n = 283) aged 28-49 years as the young adult reference group, with mean (SD) values for HGS 28 (±6) kg and MQ 12 (±3) kg/kg. The prevalence of low (T-score < -2) HGS and MQ for women 80 years and older was 52.2% and 39.6%, respectively. In multivariable models, age-adjusted HGS was associated with FMI (B = -0.13, P = 0.004) and ALMI (1.03, <0.001) while age-adjusted MQ was associated with BMI (-0.15, <0.001) but not with FMI. In a sensitivity analysis, the same pattern remained after the removal of 129 women who reported hand and/or arm pain. CONCLUSIONS: Mean HGS and MQ declined with advancing age in older women. Our data suggest that while mean HGS increased with appendicular lean mass and decreased with body fat mass, there was no association with BMI. By contrast, MQ decreased with increasing BMI, but not with increasing adiposity.

Molecular editing of cellular responses by the high-affinity receptor for IgE.

Cellular responses elicited by cell surface receptors differ according to stimulus strength. We investigated how the high-affinity receptor for immunoglobulin E (IgE) modulates the response of mast cells to a high- or low-affinity stimulus. Both high- and low-affinity stimuli elicited similar receptor phosphorylation; however, differences were observed in receptor cluster size, mobility, distribution, and the cells' effector responses. Low-affinity stimulation increased receptor association with the Src family kinase Fgr and shifted signals from the adapter LAT1 to the related adapter LAT2. LAT1-dependent calcium signals required for mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced, altering immune cell recruitment at the site of inflammation. These findings uncover how receptor discrimination of stimulus strength can be interpreted as distinct in vivo outcomes.

Pain beliefs and pain management of oncology patients.

Cancer pain is estimated to occur in 30% to 70% of patients with early-stage cancer and 60% to 95% with advanced cancer. Current research shows that cancer pain continues to be undertreated despite the availability of analgesics and established guidelines to maximize their effectiveness. The purpose of this study was to describe oncology patients' pain experience during an episode of hospitalization with particular emphasis on exploring the relationship between oncology patients' beliefs about pain and the treatment they received. Consecutive patients (n = 126) were interviewed 48 hours after admission to an urban and a regional hospital in Australia; 47.6% of patients had experienced moderate to severe pain in the previous 24 hours but had only received 40.4% of available analgesic. Patients held varying beliefs about pain and pain treatments in particular, 41% held strong beliefs about the potential for addiction to narcotics. Patients who held this belief reported higher current pain, worst pain intensity, and higher average pain intensity in the previous 24 hours. Effective pain management in the inpatient oncology setting continues to be an important clinical issue, and patients do not receive all available pain treatment. There may be an important association between patients' beliefs about pain and pain management and the pain management they receive.