Biomedical subjects

Lucy R Wedderburn

Publications and source records attributed to Lucy R Wedderburn.

11 recordsLinked to original sources

PubMed2026

Efforts towards a precision medicine approach in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the commonest group of childhood arthritides. Despite the availability of advanced therapeutics, many children and young people (CYP) with JIA experience disease flares, and in some, chronic joint damage. Tailoring treatment based on unique biological profiles would benefit CYP with JIA given their variable clinical presentation and disease course. To date, biomarkers to predict treatment response are lacking. With advances in single cell technologies, we are now able to profile the genes and proteins of target tissues at unprecedented resolution to define the biological basis of disease and guide novel treatment approaches. The complex analyses and combination of biological and clinical outcome data from large datasets across disease phenotypes have become possible with the development of computational and machine learning methods. Here, we summarize the strategies to integrate data through multimodal based approaches to maximize precision medicine and research priorities for CYP with JIA.

Humans↗

PubMed2025

Penalised regression improves imputation of cell-type specific expression using RNA-seq data from mixed cell populations compared to domain-specific methods.

Gene expression studies often use bulk RNA sequencing of mixed cell populations because single cell or sorted cell sequencing may be prohibitively expensive. However, mixed cell studies may miss expression patterns that are restricted to specific cell populations. Computational deconvolution can be used to estimate cell fractions from bulk expression data and infer average cell-type expression in a set of samples (e.g., cases or controls), but imputing sample-level cell-type expression is required for more detailed analyses, such as relating expression to quantitative traits, and is less commonly addressed. Here, we assessed the accuracy of imputing sample-level cell-type expression using a real dataset where mixed peripheral blood mononuclear cells (PBMC) and sorted (CD4, CD8, CD14, CD19) RNA sequencing data were generated from the same subjects (N=158), and pseudobulk datasets synthesised from eQTLgen single cell RNA-seq data. We compared three domain-specific methods, CIBERSORTx, bMIND and debCAM/swCAM, and two cross-domain machine learning methods, multiple response LASSO and ridge, that had not been used for this task before. We also assessed the methods according to their ability to recover differential gene expression (DGE) results. LASSO/ridge showed higher sensitivity but lower specificity for recovering DGE signals seen in observed data compared to deconvolution methods, although LASSO/ridge had higher area under curves than deconvolution methods. Machine learning methods have the potential to outperform domain-specific methods when suitable training data are available.

Humans↗

PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗

PubMed2006

Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators. OBJECTIVE: To identify a panel of cytokines specifically related to the inflammatory process in JIA. METHODS: Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease. RESULTS: Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor alpha, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested. CONCLUSION: It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

Adolescent↗

PubMed2006

Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells.

This study focuses upon three chemokines, namely CCL5, CXCL10 and CCL3, which are potential novel therapeutic targets in arthritis. The aim of the study was to analyse the expression and production of these three chemokines within the joints of children with juvenile idiopathic arthritis (JIA) of the oligoarticular and polyarticular subtypes. All three of these chemokines are highly expressed at the level of mRNA, with the most significant increase in mRNA levels being demonstrated for CCL5 when compared with matched peripheral blood samples and controls. We show that high levels of all three chemokines are present in synovial fluid of children with JIA. We investigate the major source of CCL5 from inflammatory synovial cells, which we show to be CD8+ T cells. This CD8+ synovial T cell population has an unexpected phenotype that has not been described previously, being CCR7- yet predominantly CD28+ and CD45RA-. These cells contain high levels of stored intracellular CCL5, and rapid release of CCL5 takes place on T cell stimulation, without requiring new protein synthesis. In addition, we demonstrate that CCL5 is present in synovial biopsies from these patients, in particular on the endothelium of small and medium sized vessels. We believe this to be the first in depth analysis of these mediators of inflammation in JIA.

Adult↗

PubMed2005

Quantitative assessments of the effects of a single exercise session on muscles in juvenile dermatomyositis.

OBJECTIVE: To investigate the short-term effects of exercise on muscle inflammation in children with juvenile dermatomyositis (juvenile DM). Magnetic resonance imaging (MRI), muscle strength, and blood parameters were used as outcome measures. METHODS: Children with active juvenile DM, inactive juvenile DM, and healthy children were assessed for muscle strength (using myometry) and function, and MRI T2-weighted relaxation time measurement; blood was obtained from patients with juvenile DM. A standardized physiotherapy-led exercise program was completed, and the MRI was performed immediately afterwards. All children were reassessed with myometry and MRI at 30 minutes and 60 minutes, and repeat blood tests were performed at 60 minutes for the patients with juvenile DM. RESULTS: Ten children with active juvenile DM, 10 with inactive juvenile DM, and 20 healthy controls completed the study. Muscle inflammation assessed by MRI, myometry, and blood parameters did not change significantly in response to exercise either immediately after or up to 60 minutes after the exercise program in any group. CONCLUSION: In the short term, a single bout of exercise does not change the degree of inflammation within the muscles of children with active or inactive juvenile DM or in healthy children. The data suggest that, at least in this time period, there is no evidence that exercise increases the inflammation within the muscles. We propose therefore that a moderate exercise program is safe for children with juvenile DM.

Child↗

PubMed2005

Paediatric idiopathic inflammatory muscle disease: recognition and management.

The idiopathic inflammatory myopathies (IIM) of childhood are rare, multisystem autoimmune disorders, of which the most common is juvenile dermatomyositis (JDM). The criteria currently used to diagnose the paediatric IIMs, including both JDM and other childhood autoimmune conditions in which myositis may be a prominent feature, are somewhat outdated in relation to paediatric practice. Controversies surrounding the criteria for diagnosis have resulted in an international effort to define both the diagnostic and classification criteria in light of modern investigation and practice. Clinical features of these IIMs include muscle weakness and skin rash; however, these may be absent at disease onset. JDM patients require careful assessment of multiple organ systems, which can divided into musculoskeletal and extra-musculoskeletal, and examination should include validated disease measurement tools such as the Childhood Myositis Assessment Scale. Investigations include blood tests to assess generalised markers of inflammation as well as more specific markers of muscle inflammation; organ-specific investigations, such as MRI, and muscle biopsy are also often used. Treatment and management protocols include corticosteroids, methotrexate and other disease-modifying agents such as ciclosporin (cyclosporin) and intravenous immunoglobulin, as well as newer treatments such as tumour necrosis factor blockade or B-cell depletion. Management of children with JDM requires a multidisciplinary approach, including specialist physiotherapy, occupational therapy and nursing input. Two major international projects, the International Myositis and Clinical Studies Group (IMACS) and Paediatric Rheumatology International Trials Organisation (PRINTO) aim to standardise the assessment of these patients and measurement of their disease. The efforts of these large collaborative groups should provide much needed networks for mulitcentre trials in the future.

Child↗

PubMed2004

CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.

This study investigates the role of CD4(+)CD25(+) regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4(+)CD25(bright) T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4(+)CD25(bright) T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4(+)CD25(int) T cells and therefore of CD4(+)CD25(total) in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4(+)CD25(bright) T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4(+)CD25(int) T cell population. The CD4(+)CD25(bright) cells of both patient groups and the CD4(+)CD25(int) cells of pers-OA JIA patients were able to suppress responses of CD25(neg) cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4(+)CD25(bright) T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4(+)CD25(+) Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4(+)CD25(bright) T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4(+)CD25(bright) T cells. These data suggest that CD4(+)CD25(bright) Treg cells play a role in determining the patient's fate toward either a favorable or unfavorable clinical course of disease.

Adolescent↗

PubMed2004

Paediatric idiopathic inflammatory muscle disease.

The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare but serious systemic autoimmune conditions of childhood. The most common of the paediatric IIMs is juvenile dermatomyositis (JDM), while polymyositis and inclusion body myositis are rare in children. JDM has a significantly different spectrum of disease from adult dermatomyositis. Juvenile myositis can also occur as part of other systemic autoimmune diseases such as scleroderma and systemic lupus erythematosus. There has recently been significant progress towards the development and validation of tools to measure disease activity and damage in the paediatric IIMs. In addition, several new therapeutic avenues have been used to treat JDM. This review will discuss developments in the diagnostic criteria for JDM, the clinical types and course of these conditions, recent progress in disease assessment, treatment options and new developments in research into the pathogenesis of paediatric IIM.

Child↗

PubMed2004

MHC Class I overexpression on muscles in early juvenile dermatomyositis.

OBJECTIVE: To assess muscle expression of MHC Class I complexes (heavy chain and beta2-microglobulin) and to analyze the composition of infiltrating mononuclear cells, specifically cells that bear receptors for class I MHC molecules, in the muscles of children with early juvenile dermatomyositis (JDM). METHODS: Light microscopic and immunohistochemical analysis of muscle biopsies from 10 patients with JDM and 3 controls. The mean duration from initial weakness was 2.8 months. At the time of biopsy, 9 patients had not received steroid treatment or immunomodulatory drugs. RESULTS: MHC Class I over-expression was evident on muscle fibers in all 10 JDM samples, even in a biopsy reported as normal by conventional histology. MHC class I heavy chain and beta2-microglobulin were over-expressed in an identical distribution. Variable infiltration of T cells and macrophages was seen in the JDM biopsies, with minimal lymphocytic and monocytic infiltration in 4 cases, and none in one. Only very occasional natural killer lymphocytes were identified. Neuronal cell adhesion molecule (NCAM, CD56) staining of regenerating muscle fibers was seen in all samples and these cells were confirmed as being of muscle origin by co-staining for dystrophin. CONCLUSION: MHC Class I over-expression is an early event in JDM, and may occur in the absence of lymphocytic infiltration and muscle damage. Immunostaining for MHC Class I could be used routinely in the assessment of muscle histology in juvenile dermatomyositis.

Adolescent↗

PubMed2002

Labeling antigen-specific CD4(+) T cells with class II MHC oligomers.

Class I MHC-peptide oligomers (MHC tetramers) have become popular reagents for the detection and characterization of antigen-specific CD8(+) T cells. Class II MHC proteins can be produced by expression in Escherichia coli followed by in vitro folding, or by native expression in insect cells; biotin can be introduced by site-specific chemical modification of cysteine, or by enzymatic modification of a peptide tag; and a variety of fluorescent streptavidin preparations can be used for oligomerization. Here we review methodologies for production of fluorescent oligomers of soluble class II MHC proteins and discuss their use in analysis of antigen-specific CD4(+) T cells. We explore the experimental conditions necessary for efficient staining of CD4(+) T cells using oligomers of class II MHC proteins, and we establish a standard protocol. Finally, we consider complications and challenges associated with these reagents, discuss the interpretation of staining results, and suggest future directions for investigation, in particular the use of MHC oligomers for the study of T cell avidity modulation.

Amino Acid Sequence↗