Recently, I was stopped in my tracks when I overheard a colleague comment that she was unaware that topically administered cyclosporine (Restasis, Allergan) increases goblet cell density.1-3 In 2000, Sall et al demonstrated increased goblet cell density vs. vehicle in Allergan’s pivotal Phase 3 study for Restasis.2 Can we sometimes become complacent with our therapeutic choices and forget their pharmacologic mechanism?
The all-powerful goblet cell
Let’s review the all-powerful goblet cell—a modified simple columnar epithelial cell—and its role in ocular surface maintenance.
In the eye, goblet cells are abundant throughout the conjunctival epithelium of the tarsus, fornix, and specialized areas such as the plica semilunaris. Contrary to conventional assumptions, the lid wiper is part of the conjunctiva. The lid wiper area contains goblet cell crypts deep in the epithelium, suitable as an internal lubrication system for reduction of friction between the lid margin and the globe.4 Lid wiper epitheliopathy, diagnosed by staining with fluorescein and rose bengal dyes, is a frequent finding when symptoms of dry eye are experienced in the absence of routine clinical dry eye findings.5
The name goblet cell derives from the characteristic shape of these cells in conventionally-fixed tissues—a narrow base and expanded apical portion looks like a goblet.
The mucus layer of the tear film
Regardless of fixation, goblet cells have a distinctly polarized morphology. Their nucleus is at the base of the cell, along with organelles such as mitochondria, endoplasmic reticulum, and golgi bodies. The remainder of the cell is filled with membrane-bound secretory granules filled with mucus. Goblet cells secrete mucus, a viscous fluid composed primarily of highly glycosylated proteins (mucins) suspended in a solution of electrolytes. The gel-like properties of mucins are given by its glycans (bound carbohydrates) attracting relatively large quantities of water.6 Mucus serves many functions, including protection against shear stress and chemical damage, and are found throughout the body in various systems notably respiratory tree. Here, they trap and eliminate particulate matter and microorganisms. Similarly, the mucus layer of the tear film provides protection to the cells of the cornea and conjunctiva from noxious agents and various pathogens.
The protein cores of mucins are synthesized in the rough endoplasmic reticulum and then transported to the golgi apparatus. To date, over 15 types of mucin protein cores, known as MUCs, have been cloned.7 Soluble mucins that are secreted by the goblet cells have an integral role in stabilizing the precorneal tear layer. Decreased mucin production by the conjunctival goblet cells is well recognized to lead to sight-threatening corneal complications. Goblet cell loss is often observed in several blinding ocular surface diseases, including Sjögren’s syndrome, Stevens–Johnson syndrome, ocular mucous membrane pemphigoid, and graft-versus-host disease where lack of a stable tear film may lead to corneal ulceration and perforation.8,9