Targeting TFH cells in human diseases and vaccination: rationale and practice.

The identification of CD4+ T cells localizing to B cell follicles has revolutionized the knowledge of how humoral immunity is generated. Follicular helper T (TFH) cells support germinal center (GC) formation and regulate clonal selection and differentiation of memory and antibody-secreting B cells, thus controlling antibody affinity maturation and memory. TFH cells are essential in sustaining protective antibody responses necessary for pathogen clearance in infection and vaccine-mediated protection. Conversely, aberrant and excessive TFH cell responses mediate and sustain pathogenic antibodies to autoantigens, alloantigens, and allergens, facilitate lymphomagenesis, and even harbor viral reservoirs. TFH cell generation and function are determined by T cell antigen receptor (TCR), costimulation, and cytokine signals, together with specific metabolic and survival mechanisms. Such regulation is crucial to understanding disease pathogenesis and informing the development of emerging therapies for disease or novel approaches to boost vaccine efficacy.

Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.

Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.

Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.

Contemplating autoimmunity in the Aegean islands.

The Greek island of Crete became host to lively discussions on immunoregulation as experts from around the world gathered for the 7th Aegean Conference on Autoimmunity in September 2015.

Dimers Aren't Forever: CD80 Breaks up with PD-L1.

Targeting the CTLA-4 and PD-1 "checkpoints" is an effective treatment for a number of cancers. In this issue of Immunity, Hui et al. reveal that interaction between a CTLA-4 ligand, CD80, and its counterpart in the PD-1 pathway, PD-L1, affects both PD-1 and CTLA-4 function, raising new questions about the biological effects of using checkpoint inhibitors alone and in combination.

T-cell help in the germinal center: homing in on the role of IL-21.

Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T-cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B-cell expression of the GC master transcription factor B-cell lymphoma 6 (Bcl-6) and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B-cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B-cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody-secreting cells (ASC), recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle re-entry and ASC differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B-cell selection and differentiation, potentially promoting autoreactive B-cell responses.

Steric Control of Luminescence in Phenyl-Substituted Trityl Radicals.

Triphenylmethyl (trityl) radicals have shown potential for use in organic optoelectronic applications, but the design of practical trityl structures has been limited to donor/radical charge-transfer systems due to the poor luminescence of alternant symmetry hydrocarbons. Here, we circumvent the symmetry-forbidden transition of alternant hydrocarbons via excited-state symmetry breaking in a series of phenyl-substituted tris(2,4,6-trichlorophenyl)methyl (TTM) radicals. We show that 3-fold phenyl substitution enhances the emission of the TTM radical and that steric control modulates the optical properties in these systems. Simple ortho-methylphenyl substitution boosts the photoluminescence quantum efficiency from 1% (for TTM) to 65% at a peak wavelength of 612 nm (for 2-T3TTM) in solution. In the crystalline solid state, the neat 2-T3TTM radical shows a remarkably high photoluminescence quantum efficiency of 25% for emission peaking at 706 nm. This has implications in the design of aryl-substituted radical structures where the electronic coupling of the substituents influences variables such as emission, charge transfer, and spin interaction.

Type 1 diabetes.

Type 1 diabetes is a chronic disease caused by autoimmune destruction of pancreatic ß cells. Individuals with type 1 diabetes are reliant on insulin for survival. Despite enhanced knowledge related to the pathophysiology of the disease, including interactions between genetic, immune, and environmental contributions, and major strides in treatment and management, disease burden remains high. Studies aimed at blocking the immune attack on ß cells in people at risk or individuals with very early onset type 1 diabetes show promise in preserving endogenous insulin production. This Seminar will review the field of type 1 diabetes, highlighting recent progress within the past 5 years, challenges to clinical care, and future directions in research, including strategies to prevent, manage, and cure the disease.

Microplastics and anthropogenic fibre concentrations in lakes reflect surrounding land use.

Pollution from microplastics and anthropogenic fibres threatens lakes, but we know little about what factors predict its accumulation. Lakes may be especially contaminated because of long water retention times and proximity to pollution sources. Here, we surveyed anthropogenic microparticles, i.e., microplastics and anthropogenic fibres, in surface waters of 67 European lakes spanning 30° of latitude and large environmental gradients. By collating data from >2,100 published net tows, we found that microparticle concentrations in our field survey were higher than previously reported in lakes and comparable to rivers and oceans. We then related microparticle concentrations in our field survey to surrounding land use, water chemistry, and plastic emissions to sites estimated from local hydrology, population density, and waste production. Microparticle concentrations in European lakes quadrupled as both estimated mismanaged waste inputs and wastewater treatment loads increased in catchments. Concentrations decreased by 2 and 5 times over the range of surrounding forest cover and potential in-lake biodegradation, respectively. As anthropogenic debris continues to pollute the environment, our data will help contextualise future work, and our models can inform control and remediation efforts.

An Age-Progression Intervention for Smoking Cessation: A Pilot Study Investigating the Influence of Two Sets of Instructions on Intervention Efficacy.

BACKGROUND: Research on age-progression facial morphing interventions for smoking cessation has not investigated the effect of different instructions for intervention delivery. The objective of this pilot study was to investigate the influence of two instruction types used to deliver the intervention on efficacy of the intervention. METHOD: Women were recruited and randomly allocated to an age-progression intervention session with (i) neutral instructions; (ii) instructions designed to reassure; or (iii) a condition that controlled for participant engagement ("control"). The conditions were delivered in a one-time procedure, after which primary (quitting intentions) and secondary (cigarettes/week, quit attempts) outcomes were measured immediately post-intervention, and at 1 and 3 months. RESULTS: Seventy-two women (M = 25.7; SD = 0.9) were recruited and randomly allocated to condition (Neutral n = 27, Reassuring n = 22, Control n = 23). Quitting intentions were higher in the Reassuring versus Control arm (3 months post-intervention, F = 4.37, p = 0.016, 95% CI [0.231, 2.539], eta2 = 0.11); quit attempts were greater in the two intervention arms (58%) versus Control (1-month post-intervention, 15%) (χ2 = 9.83, p < 0.05, OR 1.00 [0.28, 3.63]). CONCLUSIONS: Findings highlight the importance of optimising instructions to enhance intervention efficacy. TRIAL REGISTRATION: clinicaltrials.gov Record: NCT03749382.

Primary closure of fasciotomies has a reduced complication rate following compartment syndrome in the paediatric population.

PURPOSE: Currently no guidance exists within the literature regarding diagnostic criteria or the long-term outcomes for paediatric patients with acute compartment syndrome (ACS). We conducted a retrospective cohort study reviewing all cases of paediatric ACS managed at a single tertiary referral centre with the aim of characterising the factors responsible for the eventual outcomes. METHODS: The patient cohort was identified retrospectively by interrogating the hospital coding system for all paediatric patients between January 2014 and November 2022. The electronic emergency department, inpatient and operative notes as well as clinic letters for each patient were reviewed and data collected regarding presentation, associated injuries, management and subsequent complications plus length of follow-up. The data was analysed to determine if differences in presentation or management affected long term outcome. RESULTS: The final cohort consisted of 34 patients with a mean age of ten years at the time of presentation. The mean time from presentation to fasciotomy was 27.6 h (range 3.0 - 66.6). There was an overall complication rate of 37.5% with a mean follow-up period of 21 months. Patients who had direct closure of their fasciotomy wounds had a significantly lower complications rate and fewer operations compared to those who healed via other wound coverage methods or secondary intention (p < 0.05). CONCLUSIONS: Significantly higher complication rates were observed in patients who were unable to have direct wound closure following emergency fasciotomy. This information may be utilised to rationalise long term treatment plans and in counselling of patients and parents.

"Make it the done thing": an exploration of attitudes towards rest breaks, productivity and wellbeing while working from home.

OBJECTIVE: Taking regular rest breaks while working positively impacts productivity and wellbeing. While home and hybrid working styles have become a popular choice for employees, the impact of, and perceptions towards, taking breaks while working at home is poorly understood. The current research aimed to explore attitudes towards taking rest breaks while working from home and capture levels of breaks taken, wellbeing and productivity in a sample of UK white-collar workers. METHODS: A mixed method approach was applied where self-report data from an online survey were gathered from individuals (N = 140) from one organisation. Open-ended questions regarding attitudes and perceptions towards rest break behaviours were obtained. Further quantitative measures included the number of breaks taken while working from home, levels of productivity (measured by the Health and performance Presenteeism subscale) and mental wellbeing (measured by the Short Warwick-Edinburgh Mental wellbeing scale). Both quantitative and qualitative analysis approaches were applied. RESULTS: Qualitative responses indicated two overarching themes (1) Personal and (2) Organisational sat above four further themes including Movement outside, Structure of home working, Home environment and Digital presence. Additionally, quantitative findings indicated that the number of breaks taken outside was associated with positive changes in wellbeing. CONCLUSION: Employers could aim to support employees working from home in taking outside breaks through flexible working patterns, authentic leadership, and a change in company social norms around break behaviours. Such organisational changes could help to improve workforce productivity and wellbeing.

Development of the ARENA training programme for resilient performance in defense and security settings.

Defense and Security Personnel (DSP) often have to operate in the presence of stressful demands. Prior research has identified factors and processes associated with DSP being able to perform resiliently in demanding situations and settings. The aim of the present study was to develop a resilient performance training programme for UK defense and security operators. An intervention mapping (IM) method was used to guide the development of the programme. Typically, IM follows six sequential phases. In the present work, these phases were shaped by insights from prior research (e.g. systematic review and end user interviews), the input of a dedicated working group (N = 13) and from practitioner focus groups. During the IM process, the importance of programme flexibility was emphasized by practitioners. As such, the enAbling REsilieNt performAnce (ARENA) training programme was designed to be agile and include both face-to-face training and online learning modules. Theoretical behavior change principles, closely aligned to findings of earlier work on resilient defense and security performance, were used to underpin programme content and delivery. Future research should seek to gather data on the impact of the ARENA programme, in the targeted biological, psychological and social factors that previously been associated with resilient performances.

Maintaining a competitive edge: new rules for peripheral T cell homeostasis.

The contraction of T cell populations after immune responses is poorly understood. In this issue of Immunity, Singh et al. show that "deletor" T cells regulate the frequency of antigen-specific T cells by competing for shared subthreshold ligands.

Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN.

BACKGROUND: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN. METHODS: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis. RESULTS: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses. CONCLUSIONS: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Diagnostic value of routine pre-operative investigations used in combination in the diagnosis of periprosthetic joint infection.

The primary aim of this study was to assess the diagnostic accuracy of joint aspiration culture, serum C-reactive protein (CRP) and serum erythrocyte sedimentation rate (ESR), individually, and in combination for the diagnosis of periprosthetic joint infection (PJI). A consecutive patient series with pre-operative inflammatory marker levels, an aspiration culture of either hip or knee arthroplasty and intra-operative culture samples from subsequent revision surgery was compiled. This retrospective patient cohort analysis included 128 aspiration. The data were analysed to compare pre-operative aspiration cultures, serum ESR and CRP levels to the chosen gold standard for PJI diagnosis of intra-operative culture samples. A diagnostic algorithm was created using the above tests combined with clinical suspicion index. The values that had the highest sensitivity and specificity of predicting PJI were >5 for CRP and >16 for ESR. CRP used individually had the highest sensitivity and negative predictive value (NPV) of any test (75.0% and 75.9%, respectively). ESR + aspirate had the highest specificity and positive predictive value (PPV), of 100% for both. Using all three tests together the specificity and PPV were higher than the test individual values (95.3% and 85.0% respectively). Based on subgroup analyses the combination of ESR or CRP plus joint aspiration has superior PPV compared to individual tests. ESR and CRP had the highest NPV when used in isolation. An algorithm has been developed to guide clinical diagnosis.

The alpha defensin lateral flow test is effective in predicting eradication of periprosthetic joint infection after surgical debridement.

The primary aim of this study was to assess the utility of the alpha defensin lateral flow (ADLF) test for predicting the eradication of PJI after surgical debridement. The secondary aim was to describe the reliability of ADLF test in diagnosis of PJI intra- operatively. A prospective observational study was conducted in three independent orthopaedic centres. Twenty-two patients undergoing revision surgery (debridement, antibiotics and implant retention (DAIR), single or two-stage revision) for PJI were recruited, 13 female and 9 male with an average age of 64 years. Samples were collected intra-operatively at the start of the first surgical procedure and then at the completion of debridement or prior to reimplantation depending on the operation performed. These samples were tested using ADLF and then sent for microbiological analysis. The ADLF result was then compared to the corresponding culture result in order to determine the diagnostic predictive accuracy. The reliability of ADLF test to predict eradication of infection after debridement of PJI was excellent for specificity and positive predictive value (PPV) of which both where 100%, but had a poor sensitivity (14.3%) and negative predictive value (NPV) (62.5%). The reliability of ADLF test to predict PJI was poor with only a 50% sensitivity and specificity. The ADLF test has a high specificity and PPV for diagnosing eradication of infection after debridement. In contrast the ADLF testing appears to have poor diagnostic accuracy for PJI when used on intra-operative samples, prior to surgical intervention.

Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations.

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here, we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal-blocking compounds, distinguished CTLA-4 from LRBA mutations. Short-term T-cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or -trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene-sequencing approaches.

Correction to: The WOMAC score can be reliably used to classify patient satisfaction after total knee arthroplasty.

Unfortunately, Fig. 1 in the original article contained incorrect information. Hereby, the correct figure is published and we apologise for the inconvenience.