Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity.

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment.

Dysregulated lipid metabolism networks modulate T-cell function in people with relapsing-remitting multiple sclerosis.

Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing-remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4 + T cells are pathogenic in RRMS, and defective T-cell function could be mediated in part by liver X receptors (LXRs)-nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4 + T cells isolated from RRMS patients compared with healthy donors.

Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.

There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning analysis of serum metabolomic data stratified patients with RRMS from SPMS with high accuracy and a putative score was developed that stratified MS patient subsets. The top differentially expressed metabolites between SPMS versus patients with RRMS included lipids and fatty acids, metabolites enriched in pathways related to cellular respiration, notably, elevated lactate and glutamine (gluconeogenesis-related) and acetoacetate and bOHbutyrate (ketone bodies), and reduced alanine and pyruvate (glycolysis-related).

Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.

Objectives: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs).

Methods: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n = 62/46; Group 2, age = 26-49, n = 50/46; Group 3, age ≥ 50, n = 52/31) using multiple t tests.

Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study.

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.

CD8+ T-Cells in Juvenile-Onset SLE: From Pathogenesis to Comorbidities.

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.

Sex Differences in Lipid Metabolism: Implications for Systemic Lupus Erythematosus and Cardiovascular Disease Risk.

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.

Challenges in Implementing Cardiovascular Risk Scores for Assessment of Young People With Childhood-Onset Autoimmune Rheumatic Conditions.

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.

Sex differences and sex bias in human circadian and sleep physiology research.

Growing evidence shows that sex differences impact many facets of human biology. Here we review and discuss the impact of sex on human circadian and sleep physiology, and we uncover a data gap in the field investigating the non-visual effects of light in humans. A virtual workshop on the biomedical implications of sex differences in sleep and circadian physiology led to the following imperatives for future research: i) design research to be inclusive and accessible; ii) implement recruitment strategies that lead to a sex-balanced sample; iii) use data visualization to grasp the effect of sex; iv) implement statistical analyses that include sex as a factor and/or perform group analyses by sex, where possible; v) make participant-level data open and available to facilitate future meta-analytic efforts.

Metabolomics Defines Complex Patterns of Dyslipidaemia in Juvenile-SLE Patients Associated with Inflammation and Potential Cardiovascular Disease Risk.

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.

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies.

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.

Sex hormones drive changes in lipoprotein metabolism.

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.

Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults.

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment.

LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function.

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.

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.

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.

Disrupted Lipid Metabolism in Multiple Sclerosis: A Role for Liver X Receptors?

Multiple sclerosis (MS) is a chronic neurological disease driven by autoimmune, inflammatory and neurodegenerative processes leading to neuronal demyelination and subsequent degeneration. Systemic lipid metabolism is disturbed in people with MS, and lipid metabolic pathways are crucial to the protective process of remyelination. The lipid-activated transcription factors liver X receptors (LXRs) are important integrators of lipid metabolism and immunity.

Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH.

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated.

Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.

Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE.

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

[Figure: see text].

Disease-associated and patient-specific immune cell signatures in juvenile-onset systemic lupus erythematosus: patient stratification using a machine-learning approach.

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.