Academic Unit of Ophthalmology

Overview

Our major clinical and research interests are based on understanding how immune cells behave during inflammation on the surface of the eye (ocular surface disease) and in the eye (uveitis) that may lead to sight loss. Evaluation of these pathways underpins our translational research in the prevention and treatment of sight-threatening inflammation.

Our research

The Academic Unit of Ophthalmology in Birmingham is ideally placed to act as a focus for translational clinical research, where a clear understanding of how immune cells behave in inflamed microenvironments is likely to be of critical importance for future translational medicine. We run a substantial ophthalmology research group comprising clinicians, nurses, research scientists and students. We have a track record of MRC/Wellcome Trust/Fight for Sight funded PhD Clinical Training Fellowships. Our clinical and laboratory research studies form an important part of portfolio-adopted studies at the local Comprehensive Research Network (CRN).

Major clinical and research interests are based around the theme of ‘Inflammatory Mechanisms in the Ocular Microenvironment’. One focus of our research is the regulation of ocular immunity, in particular intraocular inflammation (uveitis). The restriction of immune responses in the eye protects this vital organ from pathological damage. However, it is clear that these regulating mechanisms are insufficient in patients with uveitis, where significant sight-threatening inflammation can occur. We are also evaluating pathways that lead to autoimmune ocular surface inflammation in conditions such as ocular mucous membrane pemphigoid and Stevens-Johnsons Syndrome, where inflammation may persist despite the apparent resolution of clinical signs of inflammation leading to progressive conjunctival scarring and surface failure. We have an interest in investigating immune system biology in the context of ocular inflammation and how this interrelates with (a) the defence mechanisms of the cornea and intraocular tissues to combat infection (microbial keratitis and endophthalmitis) and promotes healing and (b) resolution and persistence of inflammation in the ocular stromal microenvironment. Dovetailing from this body of work, is developing innovative clinical interventions that maintain a permissive tissue microenvironment that facilitates tissue regeneration and repair without scarring which is vital for maintaining optical clarity that is essential for sight. This extensive programme of work has been made possible by recently forging strong research links with Prof. Ann Logan, Professor of Molecular Neuroscience and Prof. Liam Grover (www.TRAILab.net), Professor of Biomaterials Science, School of Chemical Engineering. Our research portfolio allows for a strong, focussed and consistent research output that is central to a strong and vibrant academic environment supported by our funders, that currently include the Medical Research Council, the Wellcome Trust, NIHR, Action Medical Research, Guide Dogs for the Blind and Fight for Sight.

Projects

Inflammatory Mechanisms in the Ocular Environment

1)      Ocular surface, scarring, regeneration and biomaterials

Inflammation and scarring of the ocular surface may occur secondary to trauma, iatrogenic (Stevens-Johnson Syndrome), or immune-mediated disease, such as Mucous Membrane Pemphigoid and Sjögren’s Syndrome. Persistent inflammation of the ocular surface leads to fibrosis, contracture of the conjunctiva, and in more severe cases may lead to ulceration, stem cell failure, corneal scarring and sight loss.

ophthalmology-scar-smallWe have described ongoing conjunctival inflammation at a molecular level in the absence of clinically detectable inflammation using a novel technique of ocular surface impression cytology with flow cytometry (OSIC-flow) (Miss Rauz and Dr Curnow) and applied this to diseases such as SJS/TEN, MMP, GVHD and Sjögren’s Syndrome.  Corneal scarring is a leading cause of blindness worldwide and forms a WHO priority area for development of new therapies to prevent blindness. The Neurotrauma Research Group (Prof Logan) and Chemical Engineering (Prof Grover) are working closely with the Academic Unit of Ophthalmology (Miss Rauz) and the Department of Pharmacology (Prof Barnes) at the University of Birmingham to develop a highly innovative and revolutionary fluid-gel technology that enables a microenvironment with anti-fibrotic and anti-inflammatory factors that promote scarless wound healing. The research collaboration is a recipient of the highly prestigious Major Direct Pathway Finding Scheme Medical Research Council (MRC) Award to develop a sight-saving synthetic, optically-transparent, anti-scarring dressing for the prevention of corneal scarring.

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Disruption of ocular defence mechanisms following contact-lens wear, corneal trauma, herpes simplex virus, corneal anaesthesia, corneal exposure, and ocular surface disease predisposes the eye to severe corneal infection known as microbial keratitis, one of the commonest causes of worldwide blindness. The Academic Unit of Ophthalmology (Miss Rauz), NIHR Surgical Reconstruction and Microbiology Research Centre and the School of Biosciences (Dr Loman) are developing a novel non-culture technique for the molecular diagnosis of microbial keratitis using whole genome sequencing.

2)      Uveitis

The eye is made up of three main layers, an outer tough coating (sclera), a middle layer (uvea) and an inner light-sensing layer (retina). Inflammation of the uvea is known as uveitis.

ophthalmology-vzvStudies conducted by the Academic Unit of Ophthalmology (Prof PI Murray and Dr Wallace) have shown that the inflammatory process in uveitis consists of a complex interplay of host genetics, immune cells (macrophage, neutrophils, dendritic cells, T-cells), their signalling molecules (cytokines, i.e. IL-6), and environment (medications to dampen the immune system). The cause of most uveitis cases is unknown and there is no reliable diagnostic test. In collaboration with the National Institutes of Health (NIH), Bethesda, USA, Dr Wallace is developing a novel machine learning method known as the ‘super cell analysis’ to identify the differences in the blood cells of patients with uveitis and healthy volunteers which could lead to a reliable diagnostic test in the future.

ophthalmology - cmoThe Academic Unit of Ophthalmology (Prof PI Murray) is actively involved in undertaking Pharmaceutical clinical trials for new therapies for uveitis. At present this involves looking at a long acting steroid pellet that is injected into the eye funded by the Medical Research Council and National Institute for Health Research comparing two biological drugs (alpha interferon and infliximab) for the treatment of Behçet’s Disease. Developing novel imaging techniques using Optical Coherence Tomography as a validated methodology to accurately quantify inflammation inside the eye that could be used in the clinic and in drug trials forms a focus (Prof Murray, Mr Denniston). The work has recently expanded in to more qualitative research research exploring the quality of life issues that uveitis patients who have poor central vision related to their inflammation (cystoid macular oedema) experience. This would lead to the development of a Core Outcome Set of Patient Report Outcomes that could be added to the outcomes already measured in clinical trials of new drugs.

3)      Infections, immunity and Microbiome

optThe gut microbiome is important in the development and maintenance of a healthy immune system. Changes in the gut microbiome are linked to the body’s immune system misbehaving and leading to various diseases, such as inflammatory bowel disease and rheumatoid arthritis. In collaboration with Nick Loman (School of Biosciences) the group (Miss Rauz, Dr Wallace, Prof Murray) are evaluating the potential role of the gut microbiome as a driver of inflammation in inflammatory eye disease in genetically predisposed individuals, and whether gut microbiome changes with systemic treatment to dampen the immune system.

Publications

Mathewson PA, Williams GP, Watson SL, Hodson J, Bron AJ and Rauz S; OSDISS study group (2016) Defining Ocular Surface Disease Activity and Damage Indices by an International Delphi Consultation. Ocul Surf [Eput ahead of print]

Williams GP, Nightingale P, Southworth HS, Denniston AKO, Tomlins PJ, Turner S, Hamburger J, Bowman SJ, Curnow SJ and Rauz S (2016) Conjunctival neutrophils predict progressive scarring in Ocular Mucous Membrane Pemphigoid. Invest Ophthalmol Vis Sci 57(13):5457-69

Wallace GR (2014) HLA-B*51 the primary risk in Behçet disease. Proc Natl Acad Sci U S A 111(24):8706-7

Susarla R, Liu L, Walker EA, Bujalska IJ, Al-Salem JA, Williams GP, Sreekantam S, Taylor AE, Tallouzi M, Southworth HS, Murray PI, Wallace GR and Rauz S (2014) Cortisol Biosynthesis in the Human Ocular Surface Innate Immune Response. PLoS One 9(4):e94913

Research Team

Principal Investigator
Professor Philip I Murray - Professor of Ophthalmology, Institute of Inflammation and Ageing
Miss Saaeha Rauz - Clinical Senior Lecturer, Institute of Inflammation and Ageing
Dr Graham Wallace - Senior Lecturer in Immunity and Infection, Institute of Inflammation and Ageing
Dr S. John Curnow - Senior Lecturer, Institute of Inflammation and Ageing

Honorary Staff
Mr Alastair Denniston - Honorary Reader, Institute of Inflammation and Ageing
Mr Geraint Williams - Honorary Clinical Research Fellow, Institute of Inflammation and Ageing
Mr Paul Tomlins

Internal Collaborators
Professor Ann Logan - Professor of Molecular Neuroscience, Institute of Inflammation and Ageing
Professor Liam Grover - Professor in Biomaterials Science, School of Chemical Engineering
Professor Nicholas Barnes - Professor of Neuropharmacology, Institute of Clinical Sciences
Dr Nick Loman - MRC Research Fellow, School of Biosciences
Professor Simon Bowman - Consultant Rheumatologist and Honorary Professor, University Hospitals
Dr Benjamin Fisher - Institute of Inflammation and Ageing
Professor Melanie Calvert - Professor of Outcomes Methodology, Institutue of Applied Health Research
Dr Ana Poveda-Gallego
Dr Andrea Richards

Postdoctoral Researchers
Dr Robert Barry - Institute of Inflammation and Ageing
Dr Matthew Edmunds - Institute of Inflammation and Ageing
Maj Richard Blanch - Institute of Inflammation and Ageing
Dr Lisa Hill - Institute of Inflammation and Ageing

Clinical Research Fellows
Dr Liying Low - Institute of Inflammation and Ageing
Dr Gibran Butt

PhD Students
Miss Mariam Murad
Miss Mary O’Leary
Miss Emma Rathbone
Miss Muneera Al-Multrim
Miss Dalina Yusoff
Mr Mohamad Tallouzi

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