Anecdotal evidence suggests that Coronavirus disease 2019 (COVID-19), caused by the coronavirus SARS-CoV-2, exhibits differences in morbidity and mortality between sexes. Here, we present a ...meta-analysis of 3,111,714 reported global cases to demonstrate that, whilst there is no difference in the proportion of males and females with confirmed COVID-19, male patients have almost three times the odds of requiring intensive treatment unit (ITU) admission (OR = 2.84; 95% CI = 2.06, 3.92) and higher odds of death (OR = 1.39; 95% CI = 1.31, 1.47) compared to females. With few exceptions, the sex bias observed in COVID-19 is a worldwide phenomenon. An appreciation of how sex is influencing COVID-19 outcomes will have important implications for clinical management and mitigation strategies for this disease.
The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites ...can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
Display omitted
•Stool butyrate levels are reduced in patients with RA compared to healthy controls•Supplementation with butyrate suppresses arthritis severity in a mouse model•Suppression of arthritis by butyrate supplementation depends upon AhR+Bregs•Butyrate increases serotonin-derived 5-HIAA, which directly activates AhR+Bregs
The environmental signals that influence Breg function are not yet fully defined. Here, Rosser et al. demonstrate that the short-chain fatty acid butyrate supports Breg function by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA). 5-HIAA, in turn, activates the aryl-hydrocarbon receptor, a newly discovered transcriptional regulator for Bregs.
Objective
Vasculopathy is considered central to the pathogenesis of juvenile dermatomyositis (DM) and is associated with severe extramuscular manifestations. We undertook this study to investigate ...the hypothesis that the vasculopathy of juvenile DM can be noninvasively tracked by examining biomarkers of endothelial injury, subclinical inflammation, hypercoagulability, and vascular arterial stiffness.
Methods
The study population was a UK cohort of children with juvenile DM. Circulating endothelial cells (CECs) and microparticles (MPs) were identified using immunomagnetic bead extraction and flow cytometry, respectively. Plasma thrombin generation was determined using a fluorogenic assay. Cytokine and chemokine levels were measured by electrochemiluminescence. Arterial stiffness was assessed using pulse wave velocity (PWV). Results were expressed as the median and interquartile range (IQR), and statistical significance was assessed using nonparametric analyses.
Results
Ninety patients with juvenile DM and 79 healthy control subjects were included. The median age of the patients was 10.21 years (IQR 6.68–13.40), and the median disease duration was 1.63 years (IQR 0.28–4.66). CEC counts were higher in all patients with juvenile DM compared to controls (median 96 cells/ml IQR (40–192 and 12 cells/ml IQR 8–24, respectively; P < 0.0001). Circulating MP numbers were also significantly higher in patients with active juvenile DM compared to controls (median 204.7 × 103/ml IQR 87.9–412.6 and 44.3 × 103/ml IQR 15.0–249.1, respectively; P < 0.0001). MPs were predominantly of platelet and endothelial origin. Enhanced plasma thrombin generation was demonstrated in patients with active juvenile DM compared to those with inactive disease (P = 0.0003) and controls (P < 0.0001). Carotid‐radial PWV adjusted for age was increased in patients with juvenile DM compared to controls (P = 0.003).
Conclusion
We observed increased endothelial injury and increased levels of proinflammatory cytokines in patients with active juvenile DM. MP profiles reflected distinct disease activity status in juvenile DM and are markers of vascular pathology, platelet activation, and thrombotic propensity. Ongoing long‐term vascular injury may result in increased arterial stiffness in patients with juvenile DM.
The childhood-onset or juvenile idiopathic inflammatory myopathies (JIIMs) are a heterogenous group of rare and serious autoimmune diseases of children and young people that predominantly affect the ...muscles and skin but can also involve other organs, including the lungs, gut, joints, heart and central nervous system. Different myositis-specific autoantibodies have been identified that are associated with different muscle biopsy features, as well as with different clinical characteristics, prognoses and treatment responses. Thus, myositis-specific autoantibodies can be used to subset JIIMs into sub-phenotypes; some of these sub-phenotypes parallel disease seen in adults, whereas others are distinct from adult-onset idiopathic inflammatory myopathies. Although treatments and management have much improved over the past decade, evidence is still lacking for many of the current treatments and few validated prognostic biomarkers are available with which to predict response to treatment, comorbidities (such as calcinosis) or outcome. Emerging data on the pathogenesis of the JIIMs are leading to proposals for new trials and tools for monitoring disease.
In several murine models of autoimmune arthritis, Th17 cells are the dominant initiators of inflammation. In human arthritis the majority of IL-17–secreting cells within the joint express a cytokine ...phenotype intermediate between Th17 and Th1. Here we show that Th17/1 cells from the joints of children with inflammatory arthritis express high levels of both Th17 and Th1 lineage-specific transcription factors, RORC2 and T-bet. Modeling the generation of Th17/1 in vitro, we show that Th17 cells "convert" to Th17/1 under conditions that mimic the disease site, namely low TGFβ and high IL-12 levels, whereas Th1 cells cannot convert to Th17. Th17/1 cells from the inflamed joint share T-cell receptor (TCR) clonality with Th17 cells, suggesting a shared clonal origin between Th17 and Th17/1 cells in arthritis. Using CD161, a lectin-like receptor that is a marker of human Th17, we show synovial Th17 and Th17/1 cells, and unexpectedly, a large proportion of Th1 cells express CD161. We provide evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro, Th17 cells that convert to a Th1 phenotype maintain CD161 expression. In the joint CD161+ Th1 cells share features with Th17 cells, with shared TCR clonality, expression of RORC2 and CCR6 and response to IL-23, although they are IL-17 negative. We propose that the Th17 phenotype may be unstable and that Th17 cells may convert to Th17/1 and Th1 cells in human arthritis. Therefore therapies targeting the induction of Th17 cells could also attenuate Th17/1 and Th1 effector populations within the inflamed joint.
Type 1 interferons (IFN) are an antiviral cytokine family, important in juvenile onset systemic lupus erythematosus (jSLE) which is more common in females, around puberty. We report that plasmacytoid ...dendritic cells (pDC) from healthy females produced more type 1 IFN after toll like receptor (TLR) 7 signaling than males, even before puberty, but that puberty itself associated with increased production of type 1 IFN. A unique human model allows us to show that this was related to X chromosome number, and serum testosterone concentration, in a manner which differed depending on the number of X chromosomes present. In addition, we have showed that pDC were more activated in females overall, and immune cell
gene expression was higher in females after puberty. Therefore, sex hormones and X chromosome number were associated individually and interactively with the type 1 IFN response, which contributes to our understanding of why females are more likely to develop an IFN mediated disease like jSLE after puberty.
Calcinosis is a major cause of morbidity in JDM and has previously been linked to anti-NXP2 autoantibodies, younger age at disease onset and more persistent disease activity. This study aimed to ...investigate the clinical associations of anti-NXP2 autoantibodies in patients with JDM stratified by age at disease onset.
A total of 285 patients with samples and clinical data were recruited via the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-NXP2 was determined by both immunoprecipitation and ELISA. Logistic regression analysis was performed to assess the age-dependent relationship between anti-NXP2 and the development of calcinosis and disease activity measures.
We identified anti-NXP2 autoantibodies in 56 patients (20%). While in all patients younger age at disease onset was associated with an increased risk of calcinosis and this relationship was nearly linear, anti-NXP2 autoantibodies substantially increased the risk of calcinosis across all ages (P = 0.025) and were detectable prior to calcinosis development. Children with anti-NXP2 autoantibodies had a greater degree of weakness (median lowest ever Childhood Myositis Assessment Score 29.6 vs 42) and were less likely to be in remission at 2 years post-diagnosis. No difference in disease activity was seen 4 years post-diagnosis.
Children diagnosed at a young age have a high risk of calcinosis regardless of autoantibody status. However, the presence of anti-NXP2 autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity.
Chronic inflammatory arthritis in childhood is heterogeneous in presentation and course. Most forms exhibit clinical and genetic similarity to arthritis of adult onset, although at least one ...phenotype might be restricted to children. Nevertheless, paediatric and adult rheumatologists have historically addressed disease classification separately, yielding a juvenile idiopathic arthritis (JIA) nomenclature that exhibits no terminological overlap with adult-onset arthritis. Accumulating clinical, genetic and mechanistic data reveal the critical limitations of this strategy, necessitating a new approach to defining biological categories within JIA. In this Review, we provide an overview of the current evidence for biological subgroups of arthritis in children, delineate forms that seem contiguous with adult-onset arthritis, and consider integrative genetic and bioinformatic strategies to identify discrete entities within inflammatory arthritis across all ages.
Juvenile Dermatomyositis (JDM) is a systemic immune-mediated disease of childhood, characterized by muscle weakness, and a typical skin rash. Other organ systems and tissues such as the lungs, heart, ...and intestines can be involved, but may be under-evaluated. The inflammatory process in JDM is characterized by an interferon signature and infiltration of immune cells such as T cells and plasmacytoid dendritic cells into the affected tissues. Vasculopathy due to loss and dysfunction of endothelial cells as a result of the inflammation is thought to underlie the symptoms in most organs and tissues. JDM is a heterogeneous disease, and several disease phenotypes, each with a varying combination of affected tissues and organs, are linked to the presence of myositis autoantibodies. These autoantibodies have therefore been extensively studied as biomarkers for the disease phenotype and its associated prognosis. Next to identifying the JDM phenotype, monitoring of disease activity and disease-inflicted damage not only in muscle and skin, but also in other organs and tissues, is an important part of clinical follow-up, as these are key determinants for the long-term outcomes of patients. Various monitoring tools are currently available, among which clinical assessment, histopathological investigation of muscle and skin biopsies, and laboratory testing of blood for specific biomarkers. These investigations also give novel insights into the underlying immunological processes that drive inflammation in JDM and suggest a strong link between the interferon signature and vasculopathy. New tools are being developed in the quest for minimally invasive, but sensitive and specific diagnostic methods that correlate well with clinical symptoms or reflect local, low-grade inflammation. In this review we will discuss the types of (extra)muscular tissue inflammation in JDM and their relation to vasculopathic changes, critically assess the available diagnostic methods including myositis autoantibodies and newly identified biomarkers, and reflect on the immunopathogenic implications of identified markers.
Inflammatory T cells are thought to be central to the pathology of autoimmune arthritis. Th17 cells, CD4 T cells that secrete the pro-inflammatory cytokine IL-17 play a critical role in murine models ...of arthritis. Recent evidence from human studies suggests that Th17 cells may be important players in several autoimmune diseases, including seronegative arthritis in adults, childhood arthritis juvenile idiopathic arthritis (JIA). It was surprising to find that the development of Th17 cells is closely related to that of an immunoregulatory subset called regulatory T cells (Tregs). Tregs are important in the maintenance of immune homeostasis. Defects in Treg function or reduced numbers have been documented in several human autoimmune diseases, including RA and JIA. Conditions that typically favour the development of Tregs and promote tolerance can be subverted by inflammatory signals towards supporting the generation of Th17 cells. In animal models, the enhancement of Th17 cell differentiation is at the expense of Tregs, and these combined changes trigger autoimmunity. Several mechanisms have come to light that control this reciprocal relationship between Tregs and Th17 cells, including the action of pro-inflammatory cytokines such as IL-1β. Anti-rheumatic biologic therapies may offer a means of restoring the Th17/Treg balance in favour of Tregs and thereby re-establishing immune tolerance.