Leader: Professor Lucy R. Wedderburn
Professor Lucy Wedderburn is supported by the Great Ormond Street Hospital Children's Charity
- Ms Laura Kassoumeri, research study coordinator.
- Ms Natasha Makengo, CAPS study coordinator.
- Dr Kiran Nistala, clinical research fellow.
- Ms Ania Radziszewska, CAT Study Coordinator.
- Ms Anne Pesenacker, PhD student.
- Dr Simona Ursu, research assistant.
Research Funding for the group includes support from the Arthritis Research UK, Wellcome Trust, SPARKS UK, the National Institutes for Child Health (NIHR), Action Medical Research, the Henry Smith Charity and the Myositis Support group.
Our group has a major focus upon human T cell responses and immune regulation, in particular the autoimmune conditions of childhood, including Juvenile Idiopathic Arthritis (JIA) and Juvenile Dermatomyositis (JDM). We are interested in the mechanisms which allow survival and expansion of inflammatory T cells within the joint, the control of their production of cytokines and chemokines, and their contribution to disease. In tandem we have studied immune regulation and how this influences disease course and phenotype in JIA. Childhood arthritis has proved an excellent model in which to study the balance between activation and regulation in the childhood immune system.
Our early work characterised clonality of the T cell response within the joint and the key chemokines involved in their migration into the inflamed site. Key subsequent observations have included that regulatory T cells (Treg, Foxp3+ CD25 bright), are present and functional in the joint in JIA and, interestingly, that more Treg are found in those children with mild, (persistent oligoarticular) JIA, than those with severe disease. We have recently shown that although Treg are highly enriched in the joint and can inhibit cell proliferation in vitro, they may show abnormalities in the ATPse CD39 pathway, a mechanism thought to be involved in healthy immune regulation.
We also showed that the highly proinflammatory cell type, Th17 cells are more abundant than those with the more severe disease type, and that interestingly Treg and Th17 cells exist in a reciprocal relationship in the joint. Th17 cells from the joint differ from those found in healthy individuals, in that a large proportion also produce IFNg as well as other cytokines.
Recently we have focused upon Th17 cells and their ‘plasticity’ in the inflamed site, generating strong evidence that these cells can convert in vivo to Th1 cells (perhaps via a Th17/Th1 intermediate phenotype) under inflammatory conditions. In addition we have described the transcriptional and migration profile of cells these Th17/Th1 cells.
These data led to our study to reveal mechanistic differences between two clinical groups of patients, known as persistent and extended oligoarticular JIA. We aim to identify biological mechanisms and predictors of extension to severe arthritis. Such biomarkers would enable clinicians to identify children who have a high probability of extending to severe disease. We have shown that biological differences both of gene expression, as well as cell type and phenotype, between these two disease courses, pre date the clinical severity phenotype. We are now focusing in on certain mechanisms of disease severity implicated by these data. This work should lead to a translational study to test if these biomarkers can generate a predictive model able to predict extension to severe disease, and ultimately to improve treatment of JIA.
The group leads a major study, the SPARKS CHARMS (SPorts Aiding medical Research for KidS: Childhood Arthritis Response to Medication Study) which aims to define the factors which influence the response of children with JIA to the drugs methotrexate (MTX) or anti tumour necrosis factor (TNF) drugs. This interdisciplinary study is generating genetic, psychological and immunological data linked to carefully defined clinical response phenotypes, to understand the mechanisms of response to MTX, or the reasons for a failure of efficacy of MTX in JIA. Gene expression signature comparisons before and after MTX in JIA indicated that key regulatory pathways are implicated in the response to MTX. We also showed that certain genes whose mRNA levels are altered by MTX, also have genetic associations with response. When the full genetic data are available this expression data will be invaluable for correlating genotypes with gene expression and outcome and ultimately moving towards a ‘personalised medicine’ strategy for children with arthritis.
- The role of regulatory T cells (Treg) in juvenile idiopathic arthritis and their functional impact on disease course H. Moncrieffe, K. Nistala and L. R. Wedderburn
- The role of Th17 cells in juvenile idiopathic arthritis K. Nistala and L. R. Wedderburn
- T cell Plasticity in juvenile idiopathic arthritis K. Nistala and L. R. Wedderburn
- Childhood Arthritis Response to Medication Study, CHARMS: integration of novel insights into genetic, biological and psychological influences upon drug treatment in childhood arthritis, and application to clinical practice H. Moncrieffe, S. Ursu, F. Patrick, L. Kassoumeri, K. Burkle, S. Newman, P. Woo and L. R. Wedderburn, and in collaboration with Prof. W. Thomson, Manchester University.
- The mechanisms of action of Methotrexate in arthritis (MTX) H. Moncrieffe, S. Ursu and L. R. Wedderburn
- The role of CD39 in immunoregulation of arthritis H. Moncrieffe and L. R. Wedderburn
- The immunological and gene expression characteristics which distinguish persistent from extended oligoarticular juvenile idiopathic arthritis (JIA) A. Pesenacker, L. R. Wedderburn.
- Mechanisms of severity in juvenile idiopathic arthritis A. Pesenacker and L. R. Wedderburn
The group also contributes to several other major multi-centre collaborative studies including:
- Childhood Arthritis Prospective Study (CAPS) led by Prof. W. Thomson & Dr. K. Hyrich, Manchester.
- PRINTO methotrexate withdrawal in JIA led by Dr. D. Foell and PRINTO.
- UK Juvenile Arthritis Genetics Consortium UK, led by Prof. W. Thomson and Prof. P. Woo.
- Clinical Trials Group
- Inflammatory Muscle Disease Group
- Molecular Rheumatology Group
- Vasculitis and Autoinflammation Group
- Unit Publications
- Unit Home
Page last modified on 15 may 13 13:22