What causes dryness in Sjögren's syndrome patients and how can it be targeted?

Abstract

Concepts regarding what causes dryness in Sjögren's syndrome have evolved over the past decade. Inflammation in the lacrimal functional unit contributes to development of dry eye by causing dysfunction and even death of tear secreting epithelium in the lacrimal gland and conjunctiva that alters tear composition and stability. Disease-relevant inflammatory mediators have been identified and therapies targeting these mediators are beginning to emerge.

Keywords::

• cytokine
• dry eye
• inflammation
• IFN-γ
• IL-17
• Sjögren's syndrome
• T cell
• tear dysfunction

Dryness in Sjögren's syndrome results from disease of the lacrimal functional unit

Production, distribution and clearance of tears from the ocular surface are tightly regulated by the integrated lacrimal functional unit (LFU) that maintains tear stability in response to ocular surface demands via input from the sensory nerve endings in the cornea conjunctiva and eyelids [1,2]. Inflammation in the LFU contributes to development of eye irritation and keratoconjunctivitis sicca in Sjögren's syndrome (SS) by causing dysfunction and even death of tear-secreting epithelium in the lacrimal gland and conjunctiva and interrupting the feedback between its various components. Dysfunction of the LFU results in altered tear composition and tear instability.

Lacrimal gland dysfunction in SS results from multiple mechanisms, including cholinergic blockade from autoantibodies to muscarinic acetylcholine receptor 3 [3,4], inhibition of acinar secretion by inflammatory cytokines such as IL-1 [5], cytokine-mediated epithelial cell death [6,7] or replacement of acini by lymphocytes [6]. The lacrimal gland produces hundreds of factors that support and protect the ocular surface including growth factors (e.g., EGFs), antimicrobial factors (e.g., lactoferrin, defensins), anti-inflammatory factors (e.g., IL-1RA) and mucins. Significantly, reduced concentrations of many of these factors have been found in the tears of SS patients [8,9]. Reduced water secretion and increased tear solutes lead to increased tear osmolarity [10]. Loss of reflex tearing in response to ocular irritation or emotion occurs early in the disease course or as a result of altered cholinergic signaling. This renders SS patients particularly susceptible to desiccating environmental conditions [11].

Pathogenesis of ocular surface disease in SS

Patients with SS often suffer from constant and disabling eye irritation (e.g., foreign body sensation) and photophobia from their tear dysfunction and ocular surface disease. Traditionally, keratoconjunctivitis sicca was attributed to tear deficiency from their lacrimal gland disease; however, it is not uncommon for SS patients to have clinically significant ocular surface disease in the presence of normal tear production and volume. There is increasing evidence that changes in tear composition from a dysfunctional LFU and corneal/conjunctival inflammation are key factors in the pathogenesis of ocular surface epithelial disease and ocular discomfort in SS.

Ocular surface inflammation may develop from activation of stress signaling pathways in the ocular surface epithelial cells from hyperosmolar tears, desiccation or exposure to inflammatory mediators produced by immune/inflammatory cells that infiltrate the ocular surface and lacrimal gland as a result of dryness or systemic immune dysregulation. Inflammation can change epithelial phenotype, accelerate loss of apical mucin-bearing epithelial cells, increase epithelial cell death and sensitize nerve endings [12,13]. Certain inflammatory mediators have been identified that cause ocular surface epithelial disease in SS. These include the inflammatory matrix metalloproteinases (MMPs), inflammatory cytokines and T helper (Th) cell-associated cytokines. Increased production of MMP-3 and MMP-9 by ocular surface cells has been observed in SS [14,15]. MMP-9 lyses tight junction proteins found in the apical epithelium, causing disruption of corneal barrier function and exposing the nerve endings that terminate in the subapical cell layer. MMP-3 is a physiological activator of MMP-9 [14]. An elevated level of IL-6 on the ocular surface has been consistently detected [9,16]. IL-6 is well-recognized neural sensitizer and it may lower the stimulatory threshold of corneal nerves endings, rendering patients more sensitive to normal environmental stresses (low humidity, air drafts, etc,.) [17]. IL-17, produced by Th17 and γ–δ T cells, has been found to stimulate production of MMP-3 and MMP-9 and to disrupt corneal barrier in mouse models [18,19]. IFN-γ produced by NK and Th1 cells has a key role in the ocular surface disease in SS, promoting epithelial apoptosis, conjunctival goblet cell loss and increased expression of cornified envelope precursors, leading to a shift to a poorly wettable skin-like conjunctival epithelial phenotype [20–22]. Activated epithelial cells also produce chemokines that recruit immune/inflammatory cells to the ocular surface that amplify the response [23].

Targeting inflammatory pathways/mediators to treat SS dryness

Based on increased recognition of the role of inflammation in the tear dysfunction in SS, there has been a shift in treatment approach to include anti-inflammatory therapy, in addition to topical lubrication and surface protection with contact lenses. US FDA approval of topical cyclosporine emulsion a decade ago represented a major advance in treatment of tear dysfunction. Cyclosporine inhibits a variety of Th cytokines, including IFN-γ, and consistent with this activity was found to significantly increase conjunctival goblet cell density [24]. Topically, applied corticosteroids have been reported to significantly improve corneal epithelial disease, but they carry a risk of glaucoma, cataract formation and secondary infection with long-term use [25,26]. There is an unmet need for therapies targeting specific disease relevant inflammatory mediators. Mouse models of dry eye that develop ocular surface disease similar to SS have shown preservation of corneal barrier function with a topically applied MMP inhibitor [26]. Topically or systemically administered anti-IL-17 was reported to preserve corneal barrier function and topical anti-IFN-γ inhibited corneal and conjunctival epithelial apoptosis and prevented conjunctival goblet cell loss in the mouse model [18,27]. A pilot trial of topical IL-1RA showed improvement of signs and symptoms and multicenter trials of IL-1 neutralizing antibody are currently being conducted [28].

Conclusion

Evidence suggests that inflammation in the lacrimal gland and ocular surface causes dysfunction of the tear-producing cells, which results in profound reduction of tear secretion and the dryness that develops in SS. A number of key inflammatory mediators involved in the immunopathogenesis of SS have been identified, and evidence suggests that inhibition of certain factors can significantly improve ocular surface disease. Recent discoveries suggest that there is a possibility of more targeted and effective therapies for treating SS-associated dry eye in the future.

Financial & competing interests disclosure

The author has no financial interest in any material in this editorial. The author has received NIH Grant EY11915, NEI/NIH core Grant for Vision Research EY-002520-37, an unrestricted grant from Research to Prevent Blindness, New York, NY, USA, the Oshman Foundation, Houston, TX, USA, the William Stamps Farish Fund, Houston, TX, USA, Hamill Foundation, Houston, TX, USA. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.