Goblet cells’ role in tear stability and ocular surface health

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.

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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

Next: Conditions associated with goblet cell damage

Conditions associated with goblet cell damage

There are a number of other associated conditions in goblet cell damage: glaucoma drug therapy has been demonstrated to reduce goblet cell density.⁸ Also, the photoxic effects of an operating microscope on the ocular surface (and goblet cells) has also been established.¹⁰

Not surprisingly, a reduced number of goblet cells has been noted in Graves ophthalmopathy as compared to normal patients.¹¹

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Pseudoexfoliation seems to alter basic features of goblet cell morphology and tear stability.¹² Reduced post-operative goblet cell density has also been suggested to be one of the pathogenic factors that cause ocular discomfort and dry eye syndrome after cataract surgery.¹³

Finally, a Harvard murine goblet cell culture study demonstrated that inflammatory cytokines, such as those associated with Sjogren’s syndrome, contribute to ocular surface pathology by inducing apoptosis and altering mucin secretion and proliferation of conjunctival goblet cells.¹⁴

All hail and protect the goblet cell, essential to tear stability and ocular surface health!

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References:

1. Pflugfelder SC, De Paiva CS, Villarreal AL, et al. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008 Jan;27(1):64-9.

2. Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000 Apr;107(4):631-9.

3. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. 2002 Mar;120(3):330-7.

4. Knop N, Korb DR, Blackie CA, et al. The lid wiper contains goblet cells and goblet cell crypts for ocular surface lubrication during the blink. Cornea. 2012 June;31(6):668-79.

5. Korb DR, Herman JP, Greiner JV, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005 Jan;31(1):2-8.

6. Johansson ME, Sjövall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):352-61.

7. De Paiva CS, Raince JK, McClellan AJ, et al. Homeostatic control of conjunctival mucosal goblet cells by NKT-derived IL-13. Mucosal Immunol. 2011 Jul:4(4):397-408.

8. Aydin Kurna S, Acikgoz S, Altun A, et al. The effects of topical antiglaucoma drugs as monotherapy on the ocular surface: a prospective study. J Ophthalmol. 2014;2014:460483.

9. Pflugfelder SC, Tseng SCG, Yoshino K, et al. Correlation of goblet cell density and mucosal epithelial membrane mucin expression with rose bengal staining in patients with ocular irritation. Ophthalmology. 1997 Feb;104(2):223-35.

10. Hwang HB, Kim HS. Phototoxic effects of an operating microscope on the ocular surface and tear film. Cornea. 2014 Jan;33(1):82-90.

11. Wei YH1, Chen WL, Hu FR, et al. In vivo confocal microscopy of bulbar conjunctiva in patients with Graves' ophthalmopathy. J Formos Med Assoc. 2013 Nov 11.

12. Kozobolis VP, Christodoulakis EV, Naoumidi II, et al. Study of conjunctival goblet cell morphology and tear film stability in pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol. 2004 Jn;242(6):478-83.

13. Oh T, Jung Y, Chang D, Kim J, et al. Changes in the tear film and ocular surface after cataract surgery. Jpn J Ophthalmol. 2012 Mar;56(2):113-8.

14. Contreras-Ruiz L, Ghosh-Mitra A, Shatos MA, et al. Modulation of conjunctival goblet cell function by inflammation cytokines. Mediators Inflamm. 2013;2013:636812.