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Summary: B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis. [Copyright &y& Elsevier]

Membrane lipid microdomains (lipid rafts) play an important role in T cell function by forming areas of high lipid order that facilitate activation. However, their role in regulating T cell differentiation and function remains controversial. In this study, by applying a new approach involving microscopy and flow cytometry, we characterize membrane lipid order in ex vivo primary human CD4+ T cells. We reveal that differential membrane lipid order dictates the response to TCR stimulation. T cells with high membrane order formed stable immune synapses and proliferated robustly, intermediate order cells had reduced proliferative ability accompanied by unstable immune synapse formation, whereas low order T cells were profoundly unresponsive to TCR activation. We also observed that T cells from patients with autoimmune rheumatic disease had expanded intermediate order populations compared with healthy volunteers. This may be important in dictating the nature of the immune response since most IFN-γ+CD4+ T cells were confined within intermediate membrane order populations, whereas IL-4+CD4+ T cells were contained within the high order populations. Importantly, we were able to alter T cell function by pharmacologically manipulating membrane order. Thus, the results presented from this study identify that ex vivo CD4+ T cells sustain a gradient of plasma membrane lipid order that influences their function in terms of proliferation and cytokine production. This could represent a new mechanism to control T cell functional plasticity, raising the possibility that therapeutic targeting of membrane lipid order could direct altered immune cell activation in pathology. [ABSTRACT FROM AUTHOR]

Objective: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator-led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as the primary outcome., Methods: Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression., Results: Baseline CIMT stratified patients with JSLE (N = 151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease risk based on recommended assessment criteria. In the placebo group (n = 60), patients with high versus low CIMT progression had higher total (P = 0.001) and low-density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 80.7%). Patients treated with atorvastatin (n = 61) had reduced LDL cholesterol levels after 36 months, as expected; however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting nonlipid drivers of atherosclerosis in JSLE with management implications for this subset of patients., Conclusion: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some patients with JSLE with relevance for clinical trial stratification., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterised by immune dysregulation affecting multiple organs. Current anti-inflammatory treatments used in SLE are associated with unwanted side-effects. Dietary supplementation has been suggested as a safe and effective addition to conventional treatment, but evidence of efficacy in SLE or preventing associated comorbidities is uncertain., Methods: We identified literature on clinical trials focused on nutritional interventions in SLE aiming to improve inflammation and comorbidities. A systematic-type search on Embase, Medline, and the Cochrane Library, was conducted to identify nutritional interventions among SLE patients in the past 15 years that met our inclusion criteria., Results: We identified 2754 articles, of which 14 were eligible for inclusion based on our set criteria and were subsequently quality assessed. Vitamin D or E supplementation was associated with respective improvement of inflammatory markers or antibody production, but not disease activity scores in most studies. Despite their expected synergistic actions, the addition of curcumin on vitamin D supplementation had no additional effects on disease activity or inflammatory markers. Trials of omega-3 fatty acid supplementation presented significant reductions in ESR, CRP, disease activity, inflammatory markers, and oxidative stress, and improved lipid levels and endothelial function, while a low glycaemic index (GI) diet showed evidence of reduced weight and improved fatigue in patients., Conclusions: Different dietary guidelines can therefore be implicated to target specific SLE symptoms or therapeutic side-effects. This systematic review highlights the scarcity of larger and longer in duration trials with homogenous methodologies and verifiable outcomes to assess disease progression.

Background: Sexual dimorphisms, which vary depending on age group and pubertal status, have been described across both the innate and adaptive immune system. We explored the influence of sex hormones on immune phenotype in the context of adolescent health and autoimmunity., Methods: In this cross-sectional study, healthy, post-pubertal cisgender individuals (aged 16-25 years); healthy, pre-pubertal cisgender individuals (aged 6-11 years); transgender individuals (aged 18-19 years) undergoing gender-affirming treatment (testosterone in individuals assigned female sex at birth and oestradiol in individuals assigned male sex at birth); and post-pubertal cisgender individuals (aged 14-25 years) with juvenile-onset systemic lupus erythematosus (SLE) age-matched to cisgender individuals without juvenile-onset SLE were eligible for inclusion. Frequencies of 28 immune-cell subsets (including different T cell, B cell, and monocyte subsets) from each participant were measured in peripheral blood mononuclear cells by flow cytometry and analysed by balanced random forest machine learning. RNA-sequencing was used to compare sex and gender differences in regulatory T (Treg) cell phenotype between participants with juvenile-onset SLE, age-matched cis-gender participants without the disease, and age matched transgender individuals on gender-affirming sex hormone treatment. Differentially expressed genes were analysed by cluster and pathway analysis. Suppression assays assessed the anti-inflammatory function of Treg cells in vitro., Findings: Between Sept 5, 2012, and Nov 6, 2019, peripheral blood was collected from 39 individuals in the post-pubertal group (17 [44%] cisgender men, mean age 18·76 years [SD 2·66]; 22 [56%] cisgender women, mean age 18·59 years [2·81]), 14 children in the cisgender pre-pubertal group (seven [50%] cisgender boys, mean age 8·90 [1·66]; seven [50%] cisgender girls, mean age 8·40 [1·58]), ten people in the transgender group (five [50%] transgender men, mean age 18·20 years [0·47]; five [50%] transgender women, mean age 18·70 years [0·55]), and 35 people in the juvenile-onset SLE group (12 [34%] cisgender men, mean age 18·58 years [2·35]; 23 [66%] cisgender women, mean age 19·48 [3·08]). Statistically significantly elevated frequencies of Treg cells were one of the top immune-cell features differentiating young post-pubertal cisgender men from similarly aged cisgender women (p=0·0097). Treg cells from young cisgender men had a statistically significantly increased suppressive capacity in vitro compared with those from cisgender women and a distinct transcriptomic signature significantly enriched for genes in the PI3K-AKT signalling pathway. Gender-affirming sex hormones in transgender men and transgender women induced multiple statistically significant changes in the Treg-cell transcriptome, many of which enriched functional pathways that overlapped with those altered between cisgender men and cisgender women, highlighting a hormonal influence on Treg-cell function by gender. Finally, sex differences in Treg-cell frequency were absent and suppressive capacity was reversed in patients with juvenile-onset SLE, but sex differences in Treg-cell transcriptional signatures were significantly more pronounced in patients with juvenile-onset SLE compared with individuals without juvenile-onset SLE, suggesting that sex hormone signalling could be dysregulated in autoimmunity., Interpretation: Sex-chromosomes and hormones might drive changes in Treg-cell frequency and function. Young post-pubertal men have a more anti-inflammatory Treg-cell profile, which could explain inflammatory disease susceptibilities, and inform sex-tailored therapeutic strategies., Funding: Versus Arthritis, UK National Institute for Health Research University College London Hospital Biomedical Research Centre, Lupus UK, and The Rosetrees Trust., Competing Interests: We declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Sjögren's syndrome (SS) is a heterogeneous autoimmune rheumatic disease (ARD) characterised by dryness due to the chronic lymphocytic infiltration of the exocrine glands. Patients can also present other extra glandular manifestations, such as arthritis, anaemia and fatigue or various types of organ involvement. Due to its heterogenicity, along with the lack of effective treatments, the diagnosis and management of this disease is challenging. The objective of this review is to summarize recent multi-omic publications aiming to identify biomarkers in tears, saliva and peripheral blood from SS patients that could be relevant for their better stratification aiming at improved treatment selection and hopefully better outcomes. We highlight the relevance of pro-inflammatory cytokines and interferon (IFN) as biomarkers identified in higher concentrations in serum, saliva and tears. Transcriptomic studies confirmed the upregulation of IFN and interleukin signalling in patients with SS, whereas immunophenotyping studies have shown dysregulation in the immune cell population frequencies, specifically CD4 + and C8 + T activated cells, and their correlations with clinical parameters, such as disease activity scores. Lastly, we discussed emerging findings derived from different omic technologies which can provide integrated knowledge about SS pathogenesis and facilitate personalised medicine approaches leading to better patient outcomes in the future.

Background: The COVID-19 pandemic is an unprecedented global public health crisis that continues to exert immense pressure on healthcare and related professional staff and services. The impact on staff wellbeing is likely to be influenced by a combination of modifiable and non-modifiable factors., Objectives: The aim of this study is to evaluate the effect of the COVID-19 pandemic on the self-reported wellbeing, resilience, and job satisfaction of National Health Service (NHS) and university staff working in the field of healthcare and medical research., Methods: We conducted a cross sectional survey of NHS and UK university staff throughout the COVID-19 pandemic between May-November 2020. The anonymous and voluntary survey was disseminated through social media platforms, and via e-mail to members of professional and medical bodies. The data was analyzed using descriptive and regression (R) statistics., Results: The enjoyment of work and satisfaction outside of work was significantly negatively impacted by the COVID-19 pandemic for all of staff groups independent of other variables. Furthermore, married women reporting significantly lower wellbeing than married men ( P = 0.028). Additionally, the wellbeing of single females was significantly lower than both married women and men ( P = 0.017 and P < 0.0001, respectively). Gender differences were also found in satisfaction outside of work, with women reporting higher satisfaction than men before the COVID-19 pandemic ( P = 0.0002)., Conclusion: Our study confirms that the enjoyment of work and general satisfaction of staff members has been significantly affected by the first wave of the COVID-19 pandemic. Interestingly, being married appears to be a protective factor for wellbeing and resilience but the effect may be reversed for life satisfaction outside work. Our survey highlights the critical need for further research to examine gender differences using a wider range of methods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Peng, Wu, Doolan, Choudhury, Mehta, Khatun, Hennelly, Henty, Jury, Liao and Ciurtin.)

Diagnosis of systemic lupus erythematosus (SLE) in childhood [juvenile-onset (J) SLE], results in a more severe disease phenotype including major organ involvement, increased organ damage, cardiovascular disease risk and mortality compared to adult-onset SLE. Investigating early disease course in these younger JSLE patients could allow for timely intervention to improve long-term prognosis. However, precise mechanisms of pathogenesis are yet to be elucidated. Recently, CD8+ T-cells have emerged as a key pathogenic immune subset in JSLE, which are increased in patients compared to healthy individuals and associated with more active disease and organ involvement over time. CD8+ T-cell subsets have also been used to predict disease prognosis in adult-onset SLE, supporting the importance of studying this cell population in SLE across age. Recently, single-cell approaches have allowed for more detailed analysis of immune subsets in JSLE, where type-I IFN-signatures have been identified in CD8+ T-cells expressing high levels of granzyme K. In addition, JSLE patients with an increased cardiometabolic risk have increased CD8+ T-cells with elevated type-I IFN-signaling, activation and apoptotic pathways associated with atherosclerosis. Here we review the current evidence surrounding CD8+ T-cell dysregulation in JSLE and therapeutic strategies that could be used to reduce CD8+ T-cell inflammation to improve disease prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ciurtin, Pineda-Torra, Jury and Robinson.)

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS leading to demyelination and axonal degeneration. An increasing body of evidence suggests that lipid metabolism is associated with adverse clinical and MRI outcomes in MS. In this review we summarize the findings of association between low-density lipoproteins (LDL), high-density lipoproteins (HDL), their apolipoproteins and oxysterols with clinical and radiological disease activity in MS. Although the causality between disease activity in MS and abnormalities in lipid metabolism has not yet been elucidated, we suggest that advances in this field of research have the potential to improve understanding of MS pathophysiology and the identification of new treatment targets and strategies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

It is known that healthy women during childbearing years have a lower risk of cardiovascular disease (CVD) and coronary heart disease compared to age matched men. Various traditional risk factors have been shown to confer differential CVD susceptibilities by sex. Atherosclerosis is a major cause of CVD and mortality and sex differences in CVD risk could be due to reduced atherogenic low and very low-density lipoproteins (LDL and VLDL) and increased atheroprotective high density lipoproteins (HDLs) in women. In contrast, patients with systemic lupus erythematosus (SLE), a chronic inflammatory disease that predominately affects women, have an increased atherosclerotic and CVD risk. This increased CVD risk is largely associated with dyslipidaemia, the imbalance of atherogenic and atheroprotective lipoproteins, a conventional CVD risk factor. In many women with SLE, dyslipidaemia is characterised by elevated LDL and reduced HDL, eradicating the sex-specific CVD protection observed in healthy women compared to men. This review will explore this paradox, reporting what is known regarding sex differences in lipid metabolism and CVD risk in the healthy population and transgender individuals undergoing cross-sex hormone therapy, and provide evidence for how these differences may be compromised in an autoimmune inflammatory disease setting. This could lead to better understanding of mechanistic changes in lipid metabolism driving the increased CVD risk by sex and in autoimmunity and highlight potential therapeutic targets to help reduce this risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Robinson, Pineda-Torra, Ciurtin and Jury.)

Objectives: We report the results of a pilot young patient survey that targeted patients with JSLE and JDM, exploring well-being, resilience and general concern about the coronavirus disease 2019 (COVID-19) pandemic as well as self-assessment of disease activity., Methods: The survey was completed anonymously by patients who had been approached via the automatically generated hospital database between June and December 2020. In addition to disease characteristics, geographic location, education and employment level, we explored young patients' resilience, mood and feelings, mental well-being, self-assessed disease activity and general COVID-19 concerns using validated tools and visual analogue scales., Results: This pilot study found that self-perceived disease activity was the strongest predictor of COVID-19 concern, irrespective of gender, employment and education status or well-being and resilience. Generalized concerns regarding the COVID-19 pandemic were significantly higher in females, although their self-reported DASs were comparable to male respondents., Conclusion: Our findings highlight a gender bias in the generalized concern related to the COVID-19 pandemic, irrespective of the examined potential confounders. This suggests the need for further research around young patient self-reported outcomes outside hospital visits, especially in the context of gender differences and potential challenges of future pandemics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Cardio-vascular risk (CVR) stratification tools have been implemented in clinical practice to guide management decision for primary prevention of cardiovascular disease. Less is known about how we can optimally estimate the CVR in children and adolescents or about the reliability of the risk stratification tools validated in adult populations. Chronic inflammation associated with autoimmune rheumatic disease (ARD) drives an increased risk for accelerated atherosclerosis in patients of all ages. Although the research is less advanced than in adult populations, it is recognized that young people with ARDs with childhood-onset have increased CVR compared to age-matched healthy controls, as supported by studies investigating lipid biomarker profile and markers of endothelial dysfunction. Further research is needed to address the unmet need for adequate CVR identification and management strategies in young people in general, and in those with underlying chronic inflammation in particular. This perspective paper explores various challenges in adequately identifying and managing CVR in younger populations and potential directions for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ciurtin, Robinson, Pineda-Torra and Jury.)

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.

Introduction: Previous studies have reported that patients affected by systemic lupus erythematosus (SLE) are interested in using diet to treat fatigue, cardiovascular disease and other symptoms. However, to date, there is insufficient information regarding the ways for patients to modify their diet to improve SLE symptoms. We investigated the relationship between the eating patterns of SLE patients and their self-reported disease symptoms and general aspects of health., Methods: A UK-based, online survey was developed, in which patients with SLE were asked about their attitudes and experiences regarding their SLE symptoms and diet., Results: The majority (>80%) of respondents that undertook new eating patterns with increased vegetable intake and/or decreased intake of processed food, sugar, gluten, dairy and carbohydrates reported benefiting from their dietary change. Symptom severity ratings after these dietary changes were significantly lower than before (21.3% decrease, p<0.0001). The greatest decreases in symptom severity were provided by low/no dairy (27.1% decrease), low/no processed foods (26.6% decrease) and vegan (26% decrease) eating patterns (p<0.0001). Weight loss, fatigue, joint/muscle pain and mood were the most cited symptoms that improved with dietary change., Conclusion: SLE patients who changed their eating patterns to incorporate more plant-based foods while limiting processed foods and animal products reported improvements in their disease symptoms. Thus, our findings show promises in using nutrition interventions for the management of SLE symptoms, setting the scene for future clinical trials in this area. Randomised studies are needed to further test whether certain dietary changes are effective for improving specific symptoms of SLE.

Cardiovascular disease (CVD) is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE) associated with atherosclerosis. The interplay between dyslipidaemia and inflammation-mechanisms that drive atherosclerosis-were investigated retrospectively in adolescent JSLE patients using lipoprotein-based serum metabolomics in patients with active and inactive disease, compared to healthy controls (HCs). Data was analysed using machine learning, logistic regression, and linear regression. Dyslipidaemia in JSLE patients was characterised by lower levels of small atheroprotective high-density lipoprotein subsets compared to HCs. These changes were exacerbated by active disease and additionally associated with significantly higher atherogenic very-low-density lipoproteins (VLDL) compared to patients with low disease activity. Atherogenic lipoprotein subset expression correlated positively with clinical and serological markers of JSLE disease activity/inflammation and was associated with disturbed liver function, and elevated expression of T-cell and B-cell lipid rafts (cell signalling platforms mediating immune cell activation). Finally, exposing VLDL/LDL from patients with active disease to HC lymphocytes induced a significant increase in lymphocyte lipid raft activation compared to VLDL/LDL from inactive patients. Thus, metabolomic analysis identified complex patterns of atherogenic dyslipidaemia in JSLE patients associated with inflammation. This could inform lipid-targeted therapies in JSLE to improve cardiovascular outcomes.

Women have a reduced cardiovascular disease (CVD) risk compared with men, which could be partially driven by sex hormones influencing lipid levels post puberty. The interrelationship between sex hormones and lipids was explored in pre-pubertal children, young post-pubertal cis-men/women, and transgender individuals on cross-sex-hormone treatment (trans-men/women) using serum metabolomics assessing 149 lipids. High-density lipoproteins (HDL, typically atheroprotective) were significantly increased and very-low- and low-density lipoproteins (typically atherogenic) were significantly decreased in post-pubertal cis-women compared with cis-men. These differences were not observed pre-puberty and were induced appropriately by cross-sex-hormone treatment in transgender individuals, supporting that sex hormones regulate lipid metabolism in vivo . Only atheroprotective apolipoprotein (Apo)A1 expressing lipoproteins (HDL) were differentially expressed between all hormonally unique comparisons. Thus, estradiol drives a typically atheroprotective lipid profile through upregulation of HDL/ApoA1, which could contribute to the sexual dimorphism observed in CVD risk post puberty. Together, this could inform sex-specific therapeutic strategies for CVD management., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4 + T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function., Competing Interests: The authors declare no competing interest.

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8 +  T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8 + T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.

Background: Autoimmune rheumatic diseases (ARDs) are associated with a significant sex-bias, which becomes more evident post-puberty. This systematic review aims to elucidate the bidirectional relationship between puberty and ARD-related outcomes., Methods: Studies published in English until October 2019 were identified using a systematic search of endocrinology and rheumatology literature. Information was extracted on study design, sample size, demographics, puberty outcome measures, disease outcome measures, and main findings. The methodological quality of the studies included was analysed using the Newcastle-Ottawa Scale (NOS)., Results: Sixteen non-randomised studies reporting on the impact of puberty on ARD outcomes (n = 7), ARD impact on puberty-related outcomes (n = 8), or both (n = 1) have been identified. The impact of puberty on ARD outcomes were investigated in patients with juvenile idiopathic arthritis (JIA)-associated uveitis (n = 1), juvenile systemic lupus erythematosus (JSLE) (n = 5) or in healthy controls who developed adult-onset SLE (n = 1) or had non-specific symptoms (n = 1). The impact of ARD on puberty outcomes was explored in JIA (n = 4) and JSLE (n = 3). Quality assessment of studies showed a small to moderate risk of bias overall (NOS 4-9/9). Due to large heterogeneity of the studies it was not possible to perform a meta-analysis. Multiple studies reported on delayed puberty in patients with JIA/JSLE, menstrual and hormonal abnormalities, and lower height and weight than controls. Earlier (pre-pubertal) onset of JSLE was correlated with more severe disease and more need for systemic treatment., Conclusion: A bidirectional relationship exists between puberty and ARDs; however, more and better research is required to elucidate the complexity of this relationship. We propose puberty-related clinical assessments in patients with ARDs, which can improve patient outcomes and facilitate future research.

Sjögren's syndrome was considered for many years a disease of adulthood, characterised by immune infiltration of exocrine glands, leading to dryness (eg, dry mouth and eyes), which is a cardinal symptom. As of the last 20 years, it became apparent that although the disease is very rare in children, its clinical presentation differs from that of adults, posing substantial challenges to the recognition, diagnosis, and classification of patients with childhood-onset Sjögren's syndrome. This Viewpoint explores comparative classification criteria for children (not validated) and adults with Sjögren's syndrome, as well as differences in the clinical presentation of childhood-onset versus adult-onset Sjögren's syndrome, offering ideas about how we can improve the diagnosis of Sjögren's syndrome in children. A review of the role of medical history and clinical assessment, serology, glandular function assessment, and imaging, as well as salivary and lachrymal gland biopsy in the diagnosis of children with Sjögren's syndrome is included. Additionally, we provide suggestions about further research and registry data collection that is required to address the unmet needs of these patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited., Methods and Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings., Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SH, DB, JD, NS, AG, MB, DBM, NDV, ND, AD, SHBH, HPH, KI, PEHJ, ECJ, BK, AL, RL, AL, EM, CM, BMO, MR, FS, CS, DS, PD, AHM, MP, and PB declare no conflict of interest. OA reports grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, Teva and Viela Bio, and personal fees from Almirall, MedImmune, Merck Serono, and Roche. MA received speaker honoraria and/or travel grants from Biogen, Novartis, Merck Serono, and Sanofi. JA has served on scientific advisory boards for Roche, BMS, Abbvie, Nordic, Boerhinger, and Sanofi-Genzyme; he has received speaking honoraria from Pfizer, MSD, BMS, and Novartis; and he has received research grants from BMS and Pfizer. YB received speaker honoraria from Abbvie, Biogaran, Biogen, Boehringer Ingelheim, Ferring, Fresenius Kabi, Gilead, Hospira, Janssen, Lilly, Mayoli Spindler, Merck, MSD, Norgine, Pfizer, Roche, Sandoz, Sanofi, Shire, Takeda, and UCB. OB has received institutional fees for consultancy or lectures from Wyeth/Pfizer, AbBVIE, Roche, Chugai, Shering Plough, UCB, Swedish Orphan, Genevrier, Smith & Nephew, BMS, MSD, Celgene, novartis, Janssen, Sanofi, and Lilly. GC participated in advisory boards with AAA, Kéocyt, Ipsen, Novartis, Pfizer; he received honoraria for lectures from Ferring, Abbvie, Janssen,Biogen, Amgen, and Sandoz. YC has received institutional fees for consultancy or lectures from Abbvie, Celtrion, Getting, Pfizer, and Takeda. He received research grants from Takeda and Abbvie. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. TD’s institution received compensation for his talks and his consultation services on Advisory Boards or Steering Committees of Novartis Pharma, Merck, Biogen, GeNeuro, Mitsubishi Pharma, MedDay, Roche, Actelion, Celgene, and Genzyme; his institution received research support from Biogen, Novartis, and Roche. MG received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi Aventis, Shire and TEVA ratiopharm. EKH: honoraria/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme. BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; he holds part of two patents, one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. TH is a member of the Editorial Board of PLOS Medicine. MK has received funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen, Roche, and Teva ratiopharm; serves on scientific advisory boards for Biogen, Merck, and Roche; and received a research grant from Teva ratiopharm. JM has received an unrestricted research grant from Pfizer. XM has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall, and Roche. MN has received speaking honoraria from Abbvie, Adacyte, Amgen, Biogen, Ferring, Janssen, MSD, and Takeda. PN has received speaking honoraria from Biogen, Novartis, and Roche. CR has received speaking honoraria from Abbvie, Amgen, Astra Zeneca, Janssen, Glenmark, GSK, Lilly, Nordic Pharma, Novartis, Pfizer, and UCB. MS received speaker honoraria and/or travel grants from Roche, Chugai, Abbvie, BMS, UCB, Pfizer, Novartis, Janssen, Amgen, Biogen, laboratoires Fresenius, Lilly France, Medac, MSD, Sandoz, and Janssen. CT has received speaking honoraria from Abbvie, Ferring, Janssen, MSD, and Takeda. AV has received fee for lectures and advisory board from GSK, Novartis, and AstraZeneca in the last two years. CW has received institutional fees for consultancy, speaking, or research from Novartis, Biogen, Sanofi-Genzyme and Roche. SS is a former employee and has stocks and/or stock options in Novartis. TPH is an employee and shareholder of Pfizer Inc. MA has served on scientific advisory boards for Pfizer, Janssen, Celgene, Genentech/Roche, Takeda, Abbvie, MSD, Ferring, Falk, Mayoli, Tillots, Biogen, and Amgen. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis Pharma, and Roche. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). AFH has received speaker's fees from Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme. She has served as prinicipal investigator for projects, or received unrestricted research support from, Biogen Idec and Pfizer. XM has served on scientific advisory boards for BMS, GSK, Janssen, Novartis, Pfizer, and UCB.

Background: A subset of patients with severe COVID-19 develop a hyperinflammatory syndrome, which might contribute to morbidity and mortality. This study explores a specific phenotype of COVID-19-associated hyperinflammation (COV-HI), and its associations with escalation of respiratory support and survival., Methods: In this retrospective cohort study, we enrolled consecutive inpatients (aged ≥18 years) admitted to University College London Hospitals and Newcastle upon Tyne Hospitals in the UK with PCR-confirmed COVID-19 during the first wave of community-acquired infection. Demographic data, laboratory tests, and clinical status were recorded from the day of admission until death or discharge, with a minimum follow-up time of 28 days. We defined COV-HI as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 μg/L. Respiratory support was categorised as oxygen only, non-invasive ventilation, and intubation. Initial and repeated measures of hyperinflammation were evaluated in relation to the next-day risk of death or need for escalation of respiratory support (as a combined endpoint), using a multi-level logistic regression model., Findings: We included 269 patients admitted to one of the study hospitals between March 1 and March 31, 2020, among whom 178 (66%) were eligible for escalation of respiratory support and 91 (34%) patients were not eligible. Of the whole cohort, 90 (33%) patients met the COV-HI criteria at admission. Despite having a younger median age and lower median Charlson Comorbidity Index scores, a higher proportion of patients with COV-HI on admission died during follow-up (36 [40%] of 90 patients) compared with the patients without COV-HI on admission (46 [26%] of 179). Among the 178 patients who were eligible for full respiratory support, 65 (37%) met the definition for COV-HI at admission, and 67 (74%) of the 90 patients whose respiratory care was escalated met the criteria by the day of escalation. Meeting the COV-HI criteria was significantly associated with the risk of next-day escalation of respiratory support or death (hazard ratio 2·24 [95% CI 1·62-2·87]) after adjustment for age, sex, and comorbidity., Interpretation: Associations between elevated inflammatory markers, escalation of respiratory support, and survival in people with COVID-19 indicate the existence of a high-risk inflammatory phenotype. COV-HI might be useful to stratify patient groups in trial design., Funding: None., (© 2020 Elsevier Ltd. All rights reserved.)

Background: Juvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine-learning approaches to characterise the immune cell profile of patients with juvenile-onset SLE and investigate links with the disease trajectory over time., Methods: This study included patients who attended the University College London Hospital (London, UK) adolescent rheumatology service, had juvenile-onset SLE according to the 1997 American College of Rheumatology revised classification criteria for lupus or the 2012 Systemic Lupus International Collaborating Clinics criteria, and were diagnosed before 18 years of age. Blood donated by healthy age-matched and sex-matched volunteers who were taking part in educational events in the Centre for Adolescent Rheumatology Versus Arthritis at University College London (London, UK) was used as a control. Immunophenotyping profiles (28 immune cell subsets) of peripheral blood mononuclear cells from patients with juvenile-onset SLE and healthy controls were determined by flow cytometry. We used balanced random forest (BRF) and sparse partial least squares-discriminant analysis (sPLS-DA) to assess classification and parameter selection, and validation was by ten-fold cross-validation. We used logistic regression to test the association between immune phenotypes and k-means clustering to determine patient stratification. Retrospective longitudinal clinical data, including disease activity and medication, were related to the immunological features identified., Findings: Between Sept 5, 2012, and March 7, 2018, peripheral blood was collected from 67 patients with juvenile-onset SLE and 39 healthy controls. The median age was 19 years (IQR 13-25) for patients with juvenile-onset SLE and 18 years (16-25) for healthy controls. The BRF model discriminated patients with juvenile-onset SLE from healthy controls with 90·9% prediction accuracy. The top-ranked immunological features from the BRF model were confirmed using sPLS-DA and logistic regression, and included total CD4, total CD8, CD8 effector memory, and CD8 naive T cells, Bm1, and unswitched memory B cells, total CD14 monocytes, and invariant natural killer T cells. Using these markers patients were clustered into four distinct groups. Notably, CD8 T-cell subsets were important in driving patient stratification, whereas B-cell markers were similarly expressed across the cohort of patients with juvenile-onset SLE. Patients with juvenile-onset SLE and elevated CD8 effector memory T-cell frequencies had more persistently active disease over time, as assessed by the SLE disease activity index 2000, and this was associated with increased treatment with mycophenolate mofetil and an increased prevalence of lupus nephritis. Finally, network analysis confirmed the strong association between immune phenotype and differential clinical features., Interpretation: Machine-learning models can define potential disease-associated and patient-specific immune characteristics in rare disease patient populations. Immunological association studies are warranted to develop data-driven personalised medicine approaches for treatment of patients with juvenile-onset SLE., Funding: Lupus UK, The Rosetrees Trust, Versus Arthritis, and UK National Institute for Health Research University College London Hospital Biomedical Research Centre., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Plasma membrane lipid rafts are highly ordered membrane microdomains enriched for glycosphingolipids and cholesterol, which play an important role during T-cell antigen receptor (TCR) signaling. Our previous work has demonstrated that plasma membrane lipid composition is an important determinant of human CD4 + T-cell function and that defects in lipid raft expression contribute to CD4 + dysfunction in patients with autoimmunity. In this chapter we share three flow cytometry-based methods to quantitatively analyze plasma membrane lipid composition in primary human CD4 + T cells. We describe the quantification of glycosphingolipid expression using cholera toxin subunit B, cholesterol expression using filipin staining, and membrane "lipid order" using di-4-ANEPPDHQ. These methods can easily be adapted to analyze different cell types.

The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-gamma production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.