The Infection, Inflammation and Rheumatology Section (IIR) aims to encourage world-class research into understanding the mechanisms and treatment of inflammatory, immunological and infectious diseases.
Combining the Infectious Disease and Microbiology and the Rheumatology Units of old into one Section (IIR) within the III Research & Teaching Department has facilitated further collaboration between the major section PI's, including strengthening links with the clinical departments of paediatric infectious disease, microbiology, paediatric gastroenterology and paediatric rheumatology in Great Ormond Street Hospital.
The formation of this combined section, which houses six main research groups, comes at a fortuitous time in relation to evolving projects in the fields of infection, inflammation and immunity.
The ARUK Centre for Adolescent Rheumatology and the Reuben's Centre for Paediatric Virology and Metagenomics are exciting developments in the IIR Section, linking it to related research at UCL, as well as at UCLH and GOSH.
- Gastrointestinal Infection and Immunity Research Group
Diseases of the gastrointestinal (GI) tract represent a significant global public health burden. Diarrheal diseases continue to be a major cause of childhood mortality in the developing world; whilst food allergies, inflammatory, autoimmune and GI cancers are on the increase worldwide. Advances in technologies is now allowing us to investigate and appreciate the potential impact of the 'trillions of microbes; the resident microbiome' that co-exist in the GI tract on human health.
Hypothesis being tested:
"Interactions between the triad; GI mucosal immunity, the resident microbiome and antigens [harmless such as food or noxious e.g. pathogens and allergens) shape intestinal and extra-intestinal health".
Research questions underway:
1.Does the GI microbiome structure and function impact on clinical outcome in children undergoing hematopoietic stem cell transplant?
2. Define causes and consequences of Clostridium difficile colonisation and disease in hospitalised children.
3. Elucidate interactions involved in Campylobacter jejuni and Clostridium difficile disease pathogenesis.
4. Identify mechanisms that promote cow's milk allergy.
5. Generate signature faecal 'biomarker' profiles that may lend to future 'non-invasive' diagnosis of GI inflammatory status.
- Lee et al., 'Wiskott-Aldrich Syndrome Protein (WASp) regulates autophagy and inflammasome activity in innate immune cells'. 2017; Nature Commun, in press.
- Barisa et al., 'E. coli promotes human Vγ9Vδ2 T cell transition from cytokine-producing bactericidal effectors to professional phagocytic killes in a TCR-dependent manner'. 2017; Sci Rep. 7:2805.
- Jafari et al., Clostridium difficile-mediated effects on human intestinal epithelia: modelling host-pathogen interactions in a vertical diffusion chamber. 2016; Anaerobe, 37: 96-102.
- Jones et al., 'Amino-acid based formula affects GI cytokine milieu in children with non-IgE-mediated cow's milk allergy'. 2015; Clin Trans Allergy, 5: 41
- Stephenson et al., 'Glycosylated moieties' of Campylobacter jejuni Flagella modulate Dendritic Cell IL-10 expression via Siglec-10 Receptor engagement: A novel flagellin-host interaction. 2014; J Infect Dis. 210; 1487-98.
- Jafari et al., Differential host immune responses to sporadic versus outbreak C. difficile ribotype 017 strains. 2014; Infect and Immun. 82 (12): 4989-96.
The research team is greatly strengthened by strong collaborations with PIs' across GOS-ICH (N. Klein, K. Gustafsson, J. Standing, A.J. Thrasher) and Great Ormond Street Hospital (GOSH; F. Kiparissi, A. Austen, E. Cloutman-Green, J. Hartley), local (E. Allan, UCL), national (Serge Mostowy, N. Fairweather and G. Frankel, Imperial College; B. Wren and N. Dorrell, London School of Hygiene and Tropical Medicine; N. Minton, Nottingham) and international (H. Nielsen, Denmark; G. Jarvis, UCSF, USA; G. Hold, University of New South Wales, Australia) academic and industrial (Danone) colleague.
- Host-Pathogen Interactions and their Influence on Human Disease Research Group
Professor Klein's group focuses on interactions between microbes and microbial components and the human host. He is particularly concerned with host susceptibility to infection and host determinants of disease severity. Within his group there are projects addressing Hospital Acquired Infection, Meningococcal disease, HIV, the role of infection in preterm labour, sepsis, infections in immunocompromised children, fevers and Vascular disease.
The main areas of work include:
- Understanding the pathogenesis, prevention and management of sepsis including Meningococcal Disease (with Dr Garth Dixon and Dr Mark Peters).
- Studies investigating the pathogenesis and treatment of children with HIV infection. Some of this work is carried out in collaboration with the MRC clinical trials unit at UCL, the Paediatric European Network for Treatment of AIDS, and CHIVA. (Much of this work is done in collaboration with Professors Sarah Walker and Di Gibb).
- Investigating the role of infection in causing preterm labour. This work extends to investigating the mechanisms behind preventing and promoting preterm birth (with Professor Donald Peebles and Dr Anna David).
- Exploring the analyses and importance of host microbiomes in children with immunodeficiencies (with Dr Mona Bajaj-Elliott and Professor Judy Breuer).
- Investigating ways of reducing the risks of Hospital Acquired Infection (with Dr Elaine Cloutman-Green, Dr Kathryn Harris, Dr John Hartley and Dr Vanya Gant).
- Establishing the Reuben's Centre for Paediatric Virology and Metagenomics, dedicated to improving the diagnosis and management of children with Viral Infections (with Professor Judy Breuer).
- Investigating the causes and management of autoinflammatory conditions, fevers and vascular injury (with Dr Paul Brogan and Dr Mark Peters)
- Immunopathogenesis of Arthritis Research Group
The immunopathogenesis group, led by Lucy Wedderburn, has its focus on T cell immunology, the balance between inflammatory and regulatory responses, and how tolerance is lost, using childhood arthritis (known as juvenile idiopathic arthritis JIA) as a model.
In JIA, we have shown that Treg numbers are correlated to disease severity and are inversely correlated to the highly pro-inflammatory T cells, Th17 cells, which are also enriched at the site of disease; furthermore we have identified that Th17 cells can convert to Th1 cells at the inflamed site yet these ex Treg most likely still contribute to disease and tissue damage. Significant recent findings have included that a subpopulation of regulatory T cells (Treg), identified by expression of CD161, are also pro-inflammatory yet have a fully demethylated Foxp3 TSDR region.
The Wedderburn group leads the large cohort study aimed at stratified medicine in JIA, known as CHARMS (the Childhood Arthritis Response to Medication study). Within CHARMS we have identified novel pathways altered by treatment with methotrexate, demonstrated biomarkers that correlate with response to medication and completed the first ever genome wide association study of treatment with MTX in JIA. This wealth of data is now being modelled to generate predictive algorithms for use in stratified medicine trails of JIA.
- Inflammatory Muscle Disease Research Group
The Wedderburn group has a major interest in the pathology of muscle damage in childhood inflammatory myositis. This work is closely linked to our work through the Juvenile Dermatomyositis Cohort and Biomarker Study and the Juvenile Dermatomyositis Research Centre.This cohort and linked biobank is now the largest of its kind in the world and is a valuable resource available to the research community.
Early work showed that expression of MHC class l in JDM can predate inflammation and may itself cause muscle damage. In a novel murine model, we showed that early over expression of MHC in very young muscle rapidly precipitates ER stress and muscle dysfunction. To translate this understanding of muscle pathology to patients, we formed the International JDM Biopsy Consensus Group: the group has generated and validated a standardised method for the analysis of JDM biopsy material.
Our work on specific auto-antibodies in JDM has demonstrated that serological subtypes correlate with specific subphenotypes in JDM and have particular genetic associations, paving the way for stratified medicine trials of new therapies for subgroups of the disease. As part of the international consortium MYOGEN we have contributed to the first genome wide association study of myositis and are now included in the exciting new Genomics England project for rare diseases.
Our current work focuses on several aspects of immune pathogenesis in JDM including:
- Abnormalities of B cells in JDM in particular regulatory B cells (Breg)
- The genetics and function of the proteomsome in JDM and its relation to subtypes of disease
- The role of myeloid related proteins in JDM
The Juvenile Dermatomyositis Research Centre (JDRC) was founded in July 2000 through a charitable donation from the Cathal Hayes Research Foundation. The JDRC hosts the JDM Cohort and Biomarker Study (UK and Ireland), one of the largest collections of data and samples from children with JDM in the world. The study includes a network of researchers and clinicians know as the Juvenile Dermatomyositis Research Group (JDRG). The work of the JDRC and JDRG brings together a number of multidisciplinary health care professionals, scientists and others undertaking research into juvenile dermatomyositis (JDM) and other forms of inflammatory myositis in children. This expertise, combined with that of the JDRC's collaborative partners, has already lead to an increased understanding of the onset, course, prognosis and outcome of this and related diseases, with consequent improvements in prevention, management and, ideally, curative treatments. The JDRG involves 14 centres in total across the UK, and attracts many collaborative projects. The staff within the centre also administrate the European Network for Juvenile Dermatomyositis, which is a forum of specialists in this illness. The organisation aims to encourage research collaborations, essential to studying this rare disease. More information about all the research projects involved in this Network can be found on the JDRG website
- Vasculitis and Autoinflammation Research Group
This programme of translational clinical research relates to children with rare autoimmune and auto-inflammatory diseases. These include the primary systemic vasculitides, monogenic autoinflammatory diseases and neuroinflammatory diseases. The aims of this translational programme of research are to improve the classification and diagnosis of these diseases; to improve treatment; and to study late sequelae including cardiovascular disease. This programme of research has included discovery and development of biomarkers of systemic cerebral vasculitis disease activity; discovery of novel molecular events leading to thrombosis in the context of inflammatory vasculitis and childhood stroke; novel mechanisms of vasculitis pathogenesis mediated by anti-neutrophil cytoplasmic antibodies ; therapeutic trials of new medicines to treat vasculitis,autoinflammatoryand neuroinflammatory diseases in the young; and most recently application of new genetic technologies for the discovery of new monogenic autoinflammatory diseases in patients attending Great Ormond St Hospital.
This work began with initial research which sought to understand and optimise the gold standard for medium vessel vasculitis diagnosis: selective visceral arteriography. Whilst this work led to increased sensitivity of this test for the diagnosis of some forms of vasculitis (and hence earlier treatment) there was clearly room for improvement since this was an invasive test, could not be used for repeated monitoring, and lacked sensitivity. We then discovered that it was possible to diagnose and track endothelial injury using non-invasive tests: the detection of endothelial microparticles, released from the damaged endothelium into the peripheral circulation. We showed that endothelial microparticles displaying an activated phenotype (e-selectin) were elevated in the blood of children with active systemic vasculitis, and reduced with successful treatment. We then went on to refine these techniques and discovered that whole endothelial cells were released into the peripheral blood in addition to microparticles, and that microparticles contributed to the disease itself since they are pro-thrombotic. This led quickly to impact on clinical practice as a diagnostic screening test for vasculitis at Great Ormond Street Hospital, since small volumes of blood and same day test results were possible, clearly attractive test characteristics for acute paediatric practice.
Alongside these advances in vasculitis diagnosis and disease monitoring, our research has led to advances in therapeutics: specifically the use of biologic therapy and less toxic replacements for current cytotoxic immunosuppressive regimens for the treatment of childhood vasculitis (biologic therapy and Mycophenolate Mofetil), monogenic autoinflammatory diseases (anakinra and canakinumab), and systemic lupus erythematosus (rituximab).
We also have a rapidly expanding programme of genetic research and specifically have introduced a new genetic screening tool for vasculitis and autoinflammation using next generation sequencing, called the vasculitis and inflammation gene panel. A similar panel has also been recently introduced for genetic screening of neuro inflammatory diseases. Using this approach a genetic pickup rate currently sits at 32%.
Lastly, we have developed an interest in rare disease clinical trial design, and have obtained funding to set up the MYPAN trial (Mycophenolate mofetil versus cyclophosphamide for the induction of remission of childhood polyarteritis nodosa). We have assembled a group of methodologists and statisticians to establish Bayesian methodology for this trial. This is already impacting majorly in the paediatric rheumatology community and has become an example par excellence for setting up this sort of methodology.
The impact of this translational program of work relates to:
- improved disease classification, diagnosis, and disease monitoring biomarkers (endothelial microparticles and circulating endothelial cells) now used in routine clinical practice for monitoring effectiveness of therapy for children with vasculitis, and for early detection of late cardiovascular morbidity
- better outcomes for children with systemic and cerebral vasculitis who were resistant to treatment with conventional means
- potential understanding of how an important vasculitis treatment works (plasma exchange: possibly by removing pro inflammatory and prothrombotic neutrophil microparticles) 
- an appreciation of the importance of microparticle biology in the pathogenesis of vasculitis by the scientific community, the evidence for this being a whole section of the 15th International vasculitis and ANCA workshop, University of North Carolina Chapel Hill 2011, being dedicated to endothelium and microparticles, and several other invited international presentations including at the American Society of Nephrology in Philadelphia in November 2011
- Use of endothelial and neutrophil microparticles as biomarkers in clinical trials of new therapies in vasculitis, including a major international clinical trial of plasma exchange: the PEXIVAS trial.
- Setting up rare disease clinical trial design in the context of the MYPAN trial. This model is likely to be utilised for other clinical trials of rare diseases in children and adults in the UK.
- The first clinical trials in primary systemic vasculitis of the young: the MYPAN study (MMF v CYC in childhood PAN), the PEPRS study (sponsor Roche; The PEdiatric Polyangiitis Rituximab Study), the MYCYC trial (MMF Vs CYC in patients with ANCA vasculitis), and 2 clinical trials of canakinumab in CAPS in children under 4yrs (sponsor Novartis).
Our group will continue to carry out high-quality clinical based research (led by Prof Paul Brogan and Dr Eleftheriou) within the Infection, Inflammation and Rheumatology section and part of the III Department at UCL GOS ICH. We also intend to strengthen and forge new relationships between various aspects of basic science and clinical based research across sites and institutions, including international collaborations.