Inflammatory eye disease, ocular surface scarring, ocular infections, systemic drivers of ocular surface immune responses
Immune-Mediated Ocular Surface Diseases
The ocular surface is a highly specialised mucosa consisting of three distinct areas: the conjunctiva, corneo-scleral limbus and cornea. These together with adnexal structures (eyelids, lashes and lacrimal system) form an integrated functional unit that is essential for optical clarity and vision. Ocular surface diseases are a group of disorders with diverse pathogenesis where there is a failure of mechanisms responsible for maintaining a healthy protective ocular surface barrier. Disorders may be classified into diseases that are primarily the result of abnormalities of the ocular surface (nutritional, iatrogenic, trauma, immunological etc) or in which disease is secondary to abnormalities of the ocular adnexa (lid and tear film disorders, orbital and neurological diseases). Patients with immune-mediated diseases include a range of conditions such as atopic keratoconjunctivitis, blepharokeratoconjunctivitis; graft-versus-host disease, sclerokeratitis (frequently associated with autoimmune conditions such as Granulomatosis Polyangiitis or rheumatoid arthritis), Stevens-Johnson syndrome / Toxic epidermal necrolysis, Sjögren’s syndrome and non- Sjögren’s syndrome dry eye.
Persistence of Inflammation and Conjunctival Fibrosis
Inflammation and scarring of the ocular mucosal surfaces provide particular challenges; the most commonly encountered conjunctival scaring disorder being mucous membrane pemphigoid. Although rare (Incidence 1 in 1,000,000), damage to the ocular surface through inflammation leads to conjunctival fibrosis and contracture, surface ulceration, limbal epithelial stem cell failure and eventually total keratinisation with subsequent loss of sight. Progression of disease frequently occurs without manifest inflammation making clinical monitoring problematic. A key principal is to tease apart indices describing ‘activity’ of disease from ‘damage’ caused by disease; a task adopted in the clinical setting by a Birmingham-led International Delphi Consultation. Dovetailing from this is an innovative computer-designed custom made “Fornix Depth Measurer” (FDM - a small ruler designed to gauge conjunctival scarring around the eye) that is currently within the commercial manufacture pathway awaiting CE marking. At the bench-side setting, the group is optimising complimentary molecular/cellular analytical techniques to identify systemic drivers of inflammation or surrogate markers for ‘activity’ and ‘damage’ by examining samples taken not only from the surface of the eye, but also the gut (microbiome) in health and disease. Ongoing studies in this area could provide novel data on how best to diagnose ocular mucosal scarring diseases, their prognosis, and how to go about treating these blinding conditions.
Corneal scarring is the most common cause of preventable worldwide blindness with the WHO reporting 8 million new cases of corneal blindness per year with the World Health Assembly 2014-19 Action Plan for universal access to eye health setting a 25% target for the reduction of measurable avoidable visual impairment by 2019. Through multidisciplinary collaborations across Colleges, Institutes and International collaboration, the assembled team of clinicians, chemical engineers, pharmacologists and tissue regeneration experts, is evaluating technologies that may modify biological processes linked to scar formation to allow an optimal environment for corneal tissues to heal without scarring (thereby avoiding visually debilitating opacity). Such technologies include a novel biphasic particulate-gel that moves from liquid to gel under shear (blinking) and has capabilities of housing encapsulated drugs and cells for therapeutics. It also affords a biodegradable therapeutic ‘bandage’ for the prevention of corneal exposure or treatment of non-healing ulcers. The use of photoactivated chromophore with ultraviolet A light is also being explored.
Sight-threatening Ocular Infections
Infections are a leading cause of preventable worldwide blindness where infections of the cornea, comprise by far the largest group of disorders. Corneal Infection is the most common non-surgical emergency in the developed world and is associated with a significant cost burden to the NHS. In 2002, the World Health Organisation estimated that 10 million people were blind or visually impaired from corneal infection. Sanitation and hygiene are paramount, and in the developing world contaminated water is a major risk (trachoma, river blindness), whereas in the developed world, contact lens wear is the most significant contributory factor. Endophthalmitis is a group of infections affecting vitreous cavity and constitutes the most feared complication following cataract surgery – the most commonly performed surgical procedure to restore eyesight. Although rare, 1:1000 cases, post-operative endophthalmitis can result in complete loss of vision.
Current research is exploring the balance between inflammatory cell recruitment into the eye for sequestering and eradicating pathogenic organisms, whilst the recruitment and inflammatory cell migration into the optically clear ocular tissue in itself, threatens sight-loss. Regulation of these inflammatory pathways is necessary to limit damage and maintain optical clarity. Rapid diagnosis of infection is key and the group, with the School of Biosciences, is currently miniaturising techniques to maximise diagnostic yield from minimal biomass ocular samples using next generation sequencing. With the Health Economics Unit, tools are being developed for the quantification of direct costs of care, together with incorporation of clinical and patient reported outcomes to evaluate indirect costs of the long-term burden of disease and importantly, the impact of visual morbidity on the patients quality of life.