DRY EYE SYNDROME

Understanding and classifying the gene expression levels of certain ocular surface mucins that play a major role in maintaining ocular surface health may one day help to diagnose patients with dry eye more accurately than current methods, according to David J Galarreta MD, PhD. “Mucins perform an essential role in the tear film-epithelium unit and are responsible for key functions in the regulation of a healthy ocular surface. As well as their antimicrobial function, mucins are also implicated in cellular signalling, cellular adhesion and may function as osmo-sensors as well,†Dr Galarreta told delegates attending the 3rd EuCornea Congress.

Dr Galarreta, University of Valladolid, Spain, said that several studies have shown that dry eye syndrome leads to an alteration in the expression of certain ocular mucins. This paves the way to using specific mucin levels as a diagnostic marker for dry eye syndrome. “This will not only increase the accuracy of classifying patients correctly, but also significantly aid in clinical trials for the development of therapeutic agents for this prevalent ocular disease. Our job now is to define which targets are the best ones to try to modulate with drugs in order to benefit our patients,†he said.

Discussing the background to the burgeoning interest in researching ocular mucins, Dr Galarreta said that traditional concept of the tear film as being comprised of three layers, lipid, aqueous and mucous, has evolved considerably in recent years. “We are now also talking a lot about hydromucinic gel, which is a complex structure, secreted from goblet cells or mucus-secreting cells of glands and present at the apical surfaces of the epithelia. Mucins are usually classified into two main groups: secreted mucins which can be gel forming or soluble, or membrane-bound mucins,†explained Dr Galarreta.

Comprising both soluble and membrane-bound molecules, ocular surface mucins are highly glycosylated proteins which help to structure the tear film by binding both to each other and to the aqueous component of the tear film. In helping to stabilise the tear film, mucins play a key role in maintaining ocular surface health. In a normal eye, the concentration of ocular surface mucins is highest near the surface of the globe, and it gradually decreases as the tear/air interface is approached.

Focusing on the classification of mucins, Dr Galarreta said that different types of mucin perform different functions in the ocular surface. Secreted mucins are essentially clearing molecules with the ability to clear allergens, pathogens and debris from the ocular surface. They are also excellent lubricating agents with a high ability to retain water due to their highly hydrophilic character. Soluble mucins, such as MUC7, are produced mainly by the lacrimal gland and comprise the smallest mucin molecules in the tear film.

“MUC7 in particular has an additional antimicrobial activity, and its expression is reduced in contact lens wearers, what could be one of the causes of a higher incidence in microbial keratitis in these patients†he said. Gel-forming mucins, such as MUC2, MUC19 and MUC5AC, are secreted mainly by the goblet cells of the conjunctiva. 'Gel-forming mucins are dissolved in the tear film, but are larger and more interactive with other mucin molecules than soluble ones,' he said.

Membrane-associated mucins, such as MUC1, MUC4 and MUC16, are even longer molecules that have an intracellular extension that anchors them to epithelial cells. In the ocular surface epithelia, these mucins play a key role in protecting the ocular surface, providing boundary lubrication and preventing adhesion of facing cell surfaces. They may also function as osmo-sensors, although more research is needed to confirm this particular hypothesis. “The idea is that mucins can sense the osmolarity of the extracellular environment through their extracellular domain and then signal through the intracellular domain to the cell and actually change the condition of the cell,†he said.

Turning to the scientific literature, Dr Galarreta noted some previous studies have shown altered mucin levels in patients with Sjögren’s syndrome. In patients with Sjögren’s syndrome, the inflammation of tear-secreting glands combined with changes in the composition of the tear film reduces tear production and results in chronic dry eye. One study showed that the mucin MUC5AC transcripts in the conjunctival epithelium of patients with dry eye syndrome associated with Sjögren’s syndrome were significantly lower than those in normal individuals.

Another study showed significant variations in conjunctival mucin mRNA expression in contact lens wearers. Compelling evidence has also come from a prospective study carried out at the University of Valladolid and published last year in the journal of Investigative Ophthalmology & Visual Science (Vol. 52, No.11, pp. 8363-8369).

That study set out to evaluate mRNA levels of the ocular mucins MUC1, MUC2, MUC4, MUC5AC, and MUC7 in conjunctival impression cytology samples from patients with moderate to severe dry eye syndrome and compared them with a population of healthy subjects. It also investigated the use of the levels of these mucin genes as biomarkers of dry eye syndrome and subsequently as a potential diagnostic test for dry eye syndrome.

Expressions of MUC1, MUC2, MUC4, and MUC5AC were significantly lower in conjunctival epithelium of patients with dry eye syndrome compared with that in normal subjects. These results were replicated in the external control subject and patient groups. MUC1 expression levels demonstrated the greatest sensitivity (83 per cent) and specificity (87.5 per cent) among all genes tested. “The data strongly suggest that the expression levels of MUC1 may be used as a diagnostic test in dry eye syndrome for investigational and selective clinical trials,†the study authors concluded.