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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. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.
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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. CD4â +â 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 CD4â +â T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T-cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4â +â T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4â +â T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
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Linfocitos T CD4-Positivos , Metabolismo de los Lípidos , Receptores X del Hígado , Esclerosis Múltiple Recurrente-Remitente , Humanos , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Receptores X del Hígado/metabolismo , Femenino , Adulto , Masculino , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Persona de Mediana Edad , Colesterol/metabolismo , Glicoesfingolípidos/metabolismoRESUMEN
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.
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Colesterol/genética , Glicoesfingolípidos/genética , Receptores X del Hígado/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Benzoatos/farmacología , Bencilaminas/farmacología , Membrana Celular , Colesterol/inmunología , Femenino , Glucosiltransferasas/genética , Glicoesfingolípidos/biosíntesis , Glicoesfingolípidos/inmunología , Humanos , Sinapsis Inmunológicas/efectos de los fármacos , Sinapsis Inmunológicas/genética , Ligandos , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/inmunología , Receptores X del Hígado/agonistas , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/genética , Masculino , Redes y Vías Metabólicas/inmunología , Persona de Mediana Edad , Oxiesteroles/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto JovenRESUMEN
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. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. RESULTS: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group-1), increased very-low-density lipoproteins (Group-2), and increased low-density lipoproteins (Group-3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein(Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type-1 and type-2 diabetes by disease-wide association. CONCLUSIONS: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.
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[Figure: see text].
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Enfermedades de las Arterias Carótidas/sangre , Lipidómica , Lipoproteínas/sangre , Lupus Eritematoso Sistémico/sangre , Metaboloma , Enfermedad Arterial Periférica/sangre , Adulto , Anciano , Enfermedades Asintomáticas , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/etiología , Estudios de Casos y Controles , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Aprendizaje Automático , Espectroscopía de Resonancia Magnética , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/etiología , Valor Predictivo de las Pruebas , Factores de Riesgo , Adulto JovenRESUMEN
The liver X receptors (LXRs), LXRα and LXRß, are transcription factors with well-established roles in the regulation of lipid metabolism and cholesterol homeostasis. In addition, LXRs influence innate and adaptive immunity, including responses to inflammatory stimuli, proliferation and differentiation, migration, apoptosis and survival. However, the majority of work describing the role of LXRs in immune cells has been carried out in mouse models, and there are a number of known species-specific differences concerning LXR function. Here we review what is known about the role of LXRs in human immune cells, demonstrating the importance of these receptors in the integration of lipid metabolism and immune function, but also highlighting the need for a better understanding of the species, isoform, and cell-type specific effects of LXR activation.
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Inmunidad Adaptativa , Inmunidad Innata , Receptores Nucleares Huérfanos/metabolismo , Animales , Homeostasis , Humanos , Metabolismo de los Lípidos , Receptores X del Hígado , Isoformas de Proteínas/metabolismoRESUMEN
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). Serum metabolomic changes were recapitulated in the whole blood transcriptome, whereby differentially expressed genes were also enriched in cellular respiration pathways in patients with SPMS. The final gene-metabolite interaction network demonstrated a potential metabolic shift from glycolysis toward increased gluconeogenesis and ketogenesis in SPMS, indicating metabolic stress which may trigger stress response pathways and subsequent neurodegeneration.
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RATIONALE: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRα levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion. OBJECTIVE: To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions. METHODS AND RESULTS: We found that Arg1 expression is enhanced in CD68+ cells from regressive versus progressive lesions in a murine aortic arch transplant model. In cultured macrophages, ligand-activated LXRα markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXRα-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXRα-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXRα-deficient CD68+ cells. LXRα does not bind to the Arg1 promoter but instead promotes the interaction between PU.1 and interferon regulatory factor (IRF)8 transcription factors and induces their binding of a novel composite element. Accordingly, knockdown of either IRF8 or PU.1 strongly impairs LXRα regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXRα binds the IRF8 locus and its activation increases IRF8 mRNA and protein levels in these cells. CONCLUSIONS: This work implicates Arg1 in atherosclerosis regression and identifies LXRα as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXRα regulates macrophage target gene expression through PU.1 and IRF8.
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Arginasa/metabolismo , Factores Reguladores del Interferón/fisiología , Macrófagos/metabolismo , Receptores Nucleares Huérfanos/fisiología , Proteínas Proto-Oncogénicas/fisiología , Transactivadores/fisiología , Animales , Arginasa/biosíntesis , Arginasa/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Línea Celular , Marcación de Gen/métodos , Sitios Genéticos , Factores Reguladores del Interferón/antagonistas & inhibidores , Factores Reguladores del Interferón/metabolismo , Receptores X del Hígado , Macrófagos/enzimología , Ratones , Ratones Noqueados , Receptores Nucleares Huérfanos/deficiencia , Receptores Nucleares Huérfanos/genética , Unión Proteica/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismoRESUMEN
Glucocorticoid (GC) induction of the tyrosine aminotransferase (TAT) gene by the glucocorticoid receptor (GR) is a classic model used to investigate steroid-regulated gene expression. Classic studies analyzing GC-induction of the TAT gene demonstrated that despite having very high affinity for GR, some steroids cannot induce maximal TAT enzyme activity, but the molecular basis for this phenomenon is unknown. Here, we used RT-PCR and chromatin immunoprecipitation to determine TAT mRNA accumulation and GR recruitment to the TAT promoter (TAT-GRE) in rat hepatoma cells induced by seven GR ligands: dexamethasone (DEX), cortisol (CRT), corticosterone (CCS), 11-deoxycorticosterone (DOC), aldosterone (ALD), progesterone (PRG) and 17-hydroxyprogesterone (17P). As expected, DEX, CRT, CCS and ALD all induced both TAT mRNA and GR recruitment to the TAT-GRE, while PRG and 17P did not. However, while DOC could not induce significant TAT mRNA, it did induce robust GR occupancy of the TAT-GRE. DOC also induced recruitment of the histone acetyltransferase p300 to the TAT-GRE as efficiently as DEX. These DOC-induced effects recapitulated at another GR target gene (sulfonyltransferase 1A1), and DOC also failed to promote the multiple changes in gene expression required for glucocorticoid-dependent 3T3-L1 adipocyte differentiation. Structural simulations and protease sensitivity assays suggest that DOC and DEX induce different conformations in GR. Thus, although steroids that bind GR with high affinity can induce GR and p300 occupancy of target promoters, they may not induce a conformation of GR capable of activating transcription.
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Corticoesteroides/química , Regiones Promotoras Genéticas/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Activación Transcripcional/efectos de los fármacos , 17-alfa-Hidroxiprogesterona/química , 17-alfa-Hidroxiprogesterona/farmacología , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Corticoesteroides/farmacología , Aldosterona/química , Aldosterona/farmacología , Animales , Línea Celular Tumoral , Corticosterona/química , Corticosterona/farmacología , Desoxicorticosterona/química , Desoxicorticosterona/farmacología , Dexametasona/química , Dexametasona/farmacología , Hidrocortisona/química , Hidrocortisona/farmacología , Ligandos , Ratones , Estructura Molecular , Progesterona/química , Progesterona/farmacología , Conformación Proteica/efectos de los fármacos , Ratas , Receptores de Glucocorticoides/químicaRESUMEN
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.
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Enfermedades Autoinmunes/inmunología , Enfermedades Cardiovasculares/inmunología , Dislipidemias/inmunología , Metabolismo de los Lípidos/inmunología , Enfermedades Reumáticas/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Cardiovasculares/terapia , Dislipidemias/terapia , Humanos , Inflamación/inmunología , Inflamación/terapia , Enfermedades Reumáticas/terapiaRESUMEN
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.
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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.
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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.
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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. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Diabetes Mellitus Tipo 2/patología , Progresión de la Enfermedad , Fibrosis , Humanos , Inflamación/metabolismo , Resistencia a la Insulina/genética , Hígado/metabolismo , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
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.
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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.
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Caracteres Sexuales , Sexismo , Ritmo Circadiano/fisiología , Femenino , Humanos , Masculino , Sueño/fisiologíaRESUMEN
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of genes implicated in lipid homeostasis and inflammation. PPARalpha trans-activity is enhanced by recruitment of coactivators such as SRC1 and CBP/p300 and is inhibited by binding of corepressors such as NCoR and SMRT. In addition to ligand binding, PPARalpha activity is regulated by post-translational modifications such as phosphorylation and ubiquitination. In this report, we demonstrate that hPPARalpha is SUMOylated by SUMO-1 on lysine 185 in the hinge region. The E2-conjugating enzyme Ubc9 and the SUMO E3- ligase PIASy are implicated in this process. In addition, ligand treatment decreases the SUMOylation rate of hPPARalpha. Finally, our results demonstrate that SUMO-1 modification of hPPARalpha down-regulates its trans-activity through the specific recruitment of corepressor NCoR but not SMRT leading to the differential expression of a subset of PPARalpha target genes. In conclusion, hPPARalpha SUMOylation on lysine 185 down-regulates its trans-activity through the selective recruitment of NCoR.
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Co-Represor 1 de Receptor Nuclear/metabolismo , PPAR alfa/metabolismo , Proteína SUMO-1/metabolismo , Sitios de Unión , Línea Celular , Proteínas Co-Represoras/metabolismo , Regulación de la Expresión Génica , Humanos , Cinética , Lisina/metabolismo , PPAR alfa/fisiología , Transporte de ProteínasRESUMEN
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. Consequently, there is a strong interest in targeting these receptors in a number of metabolic and inflammatory diseases, including MS. We have reviewed the evidence for involvement of LXR-driven lipid metabolism in the dysfunction of peripheral and brain-resident immune cells in MS, focusing on human studies, both the relapsing remitting and progressive phases of the disease are discussed. Finally, we discuss the therapeutic potential of modulating the activity of these receptors with existing pharmacological agents and highlight important areas of future research.
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Colesterol/metabolismo , Metabolismo de los Lípidos , Receptores X del Hígado/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple/metabolismo , Animales , Encéfalo/metabolismo , Colesterol/química , Progresión de la Enfermedad , Humanos , Sistema Inmunológico , Inflamación , Lípidos/química , Hígado/metabolismo , Ratones , Ratones Noqueados , Receptores Nucleares Huérfanos/metabolismo , Oxiesteroles/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
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.
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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. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications.