Paul Brogan

Section Head

Dr Paul Brogan

Principle Investigators

Contact

Infection, Inflammation and Rheumatology
Institute of Child Health
30 Guilford Street
London WC1N 1EH

Infection, Inflammation and Rheumatology


The new 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 IIIP programme 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 new ARUK Centre for Adolescent Rheumatology and the forthcoming Reuben's Centre of Paediatric Virology are exciting developments in the IIR Section, linking it to related research at UCL, as well as at UCLH and GOSH.

Research groups

Gastrointestinal Immunity in Health and Disease Research Group

Diarrheal diseases continue to be a major cause of child mortality in the developing world. Globally, gastrointestinal (GI) inflammatory (Inflammatory Bowel Diseases, Celiac disease, Irritable bowel syndrome) conditions are on the rise. Our overarching research aim is to understand how GI mucosal immunity, the resident microbiome and harmless (food antigens) versus noxious (infections, allergens) triggers shape intestinal health.

Focus of the current programme is:

  • 1. Delineate host-pathogen cross-talk in response to (a) Campylobacter jejuni a leading cause of bacterial-induced diarrhoea worldwide; and (b) Clostridium difficile an emerging enteropathogen that represents a significant global health burden.
  • 2. How Dysbiosis (changes in microbial composition) disrupts intestinal and extra-intestinal homeostasis?
  • 3. Define pathogenesis leading to Cow’s milk allergy in the infant.
  • 4. Identify potential biomarkers for food allergy.

The research team is strengthened by strong collaborations with PIs’ across programmes at ICH/GOSH, local (E. Allan, UCL), national (B. Wren, N. Dorrell LSHTM; N. Fairweather, G. Frankel, S. Mostowy, Imperial College; N. Minton, Nottingham; G. Hold, Aberdeen) and international (H. Nielsen, Denmark; G. Jarvis, UCSF, USA; G. Nunez, U of Michigan, USA) academic and industrial (Danone) colleagues.

Researchers

  • Dr Mona Bajaj-Elliott
  • Ms Katja Brunner
  • Mr James Bonner
  • Dr Penny James
  • Dr Hannah Jones
  • Mr Enea Millioris
  • Ms Nayani Pramanik
  • Mr Mario Songane
  • Dr Intan Yeop

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 Robin Callard, Sarah Walker and Di Gibb).
  • Investigating the role of infection in causing preterm labor. 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 of Paediatric Virology. This will be 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)

Researchers

  • Prof Nigel Klein
  • Prof Judy Breuer
  • Dr Garth Dixon
  • Dr Joe Standing
  • Dr Dagmar Alber
  • Ms Lisa Carter
  • Ms Elaine Cloutman-Green
  • Mr Alastair Copland
  • Mr Ronan Doyle
  • Dr Felicity Fitzgerald
  • Ms Eva Germovsek
  • Mr Rijan Gurung
  • Dr Kathryn Harris
  • Dr David Ho
  • Mr Rollo Hoare
  • Ms Charlotte Houldcroft
  • Dr Patricia Hunter
  • Dr Hannah Jones
  • Dr Julia Kenny
  • Dr Karolena Kotowicz
  • Ms Julianne Lockwood
  • Dr Yvonne Majani
  • Mr Adedeji Majekodunmi
  • Dr Helen Payne
  • Ms Hannah Poulsom

Immunology and Mathematical Modelling Research Group

Professor Robin Callard heads a multidisciplinary group using mathematical models of T cell homeostasis to investigate immune reconstitution in HIV infected children on antiretroviral therapy with data from trials in Africa and in children following bone marrow transplantation. We have recently described a model that gives a quantitative estimate of T cell export from the thymus from simple measurements of cell proliferation with Ki67 and numbers of TRECs. This model allows the contribution of thymic export to T cell homeostasis to be quantified.   We have also developed models for T cell proliferation, which can determine proliferation and death rates from CFSE flow cytometry profiles. In collaboration with Dr Andy Yates, Albert Einstein College of Medicine, NY; Dr Rodolphe Thiebaut, INSERM Bordeaux and Dr Ben Seddon NIMR, London, these studies of T cell homeostasis are enabling experimentally testable hypothesis for CD4 depletion in HIV infection to be investigated using mechanistic models of T cell homeostasis. This work is now being complemented by high throughput sequencing of TCR α/β and γ/δ chains with the development of mathematical models to estimate and compare TCR diversity during immune reconstitution. 

Researchers

  • Professor Robin Callard
  • Dr Joe Standing
  • Miss Lisa Carter
  • Mr Rollo Hoare

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.

Researchers

  • Prof Lucy Wedderburn
  • Dr Kiran Nistala
  • Dr David Bending
  • Ms Chantal Duurland
  • Ms Eirini Giannakopoulou
  • Ms Sophie Gordon-Smith
  • Ms Hannah Lom
  • Dr Sherry Yasin

Support Staff

  • Ms Brenda Bell, Administrator, Centre for Adolescent Rheumatology
  • Mr Dominik Beste, Computer Scientist
  • Ms Hema Chaplin, Research Facilitator
  • Ms Clare Heard, CHART Study Coordinator
  • Ms Natasha Makengo, CAPS Data Manager 

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 tehrapies 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

Researchers

  • Prof Lucy Wedderburn
  • Dr Kiran Nistala
  • Dr Beverley Almeida
  • Ms Katie Arnold
  • Dr David Bending
  • Dr Sherry Yasin

Support Staff

  • Ms Katie Arnold, JDRC Administrator
  • Ms Brenda Bell, Administrator, Centre for Adolescent Rheumatology
  • Ms Yvonne Glackin, POPS Study Coordinator
  • Ms Natasha Makengo, CAPS Data Manager

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, and monogenic autoinflammatory 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 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 and autoinflammatory 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).

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:

  1. 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
  2. better outcomes for children with vasculitis who were resistant to treatment with conventional means
  3. potential understanding of how an important vasculitis treatment works (plasma exchange: possibly by removing pro inflammatory and prothrombotic neutrophil microparticles) [10]
  4. 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
  5. 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.
  6. 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.
  7. 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 within the new infection inflammation and rheumatology section (led by Dr Paul Brogan) and part of the the IIIP programme at ICH / UCL. 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.

Researchers

  • Dr Paul Brogan
  • Ms Annette Keylock
  • Prof Nigel Klein
  • Dr Despina Eleftheriou
  • Dr Ying Hong
  • Dr Sonia Melo Gomes
  • Dr Elena Moraitis
  • Dr Claire Murphy
  • Dr Sira Nanthapisal
  • Dr Ebun Omoyinmi
  • Dr Ariane Standing

Page last modified on 19 sep 14 14:21