# Emerging Trends and Management for Sjogren Syndrome-Related Dry Eye Corneal Alterations
## 3. **Glandular Ocular Involvement: Dry Eye Disease (DED) or Keratoconjunctivitis Sicca (KCS)**
### Pathogenesis  
In general, the etiopathogenesis of the pSS is not yet completely elucidated and is believed to be complex and multifactorial [45; 46]. Considering specifically the SS-related DED, many scientific data support the existence of a strong interaction amongst ocular surface components and immune and nervous systems in its onset and development [45; 46; 47]. A central factor seems to be the loss of the so-called \"immune tolerance\" or \"immune-privilege\" of the ocular surface, i.e., its ability to activate specific immunoregulatory mechanisms that prevent continuous and unnecessary inflammatory/immune responses and consequent tissue damage despite the constant exposure to various environmental stimuli [48].  
Possible mechanisms involved in the SS-related KCS pathogenesis include the following:  
* Environmental factors-triggered autoimmune attack against the lachrymal glands [49], which represent the first and most important pSS target [24; 25], leading to reduced aqueous tear film and epithelial growth factors secretion and tear film hyperosmolarity;
* Autoimmune attack against the ocular surface epithelium, conjunctival goblet cells, and Meibomian glands, with reduction in all tear film components, as well as epithelial cells autoantigens expression and proinflammatory molecules release [50];
* Amplification of the inflammatory response by innate and adaptive immune systems with the release of proinflammatory cytokine and chemokines [33; 51];
* Neuroinflammation and neurodegeneration [32; 34], with reduced tear reflex and NGFs production [40];
* Decreased levels of growth factors on the ocular surface, including epidermal growth factor secreted by the lachrymal gland, nerve growth factors (NGFs) released by the corneal nerves, and transforming growth factor produced by the conjunctival goblet cells [27], with impairment of the epithelial cell proliferation, differentiation, and migration;
* Dysbiosis of the ocular surface, which may trigger an autoimmune attack via autoantibodies-mimicry mechanisms and may increase infection susceptibility [28];Damage/apoptosis of epithelial cells, corneal dendritic cells, keratocytes, conjunctival goblet cells, and ocular surface nerves involved in the \"immune-tolerance\" of the ocular surface [48], which may favor autoantigens' presentation of T and B lymphocytes [45; 46]; Genetic and epigenetic factors may favor a dysregulated inflammatory/immune response in predisposed subjects [52; 53].  
A vicious circle of autoimmune and inflammatory responses, reduction in tear film production, ocular surface damage, and denaturation is thought to lead to a chronic, auto-maintaining, and progressive disease [45; 46; 47]. Furthermore, it is still unclear if the ocular surface inflammation and damage are primary, i.e., related to the direct autoimmune attack of the ocular surface epithelium [50], or secondary, i.e., induced by the lacrimal gland dysfunction and the consequent eye dryness [47; 54]. Tear hyperosmolarity has been indeed demonstrated to cause upregulation of the inflammatory and innate immune response and damage and dysfunction of the ocular surface epithelial and goblet cells [47; 54].  
Moreover, the significantly higher incidence of the infectious keratitis found in SS subjects, prevalently bacterial [41], may be related to several predisposing factors, including decreased tears flux, which reduces the ocular surface wash [6; 7]; lower levels of antimicrobial tear molecules, such as lactoferrin, lysozyme, and IgA [27]; corneal and conjunctival epithelial defects [12]; ocular surface microbiome dysbiosis, with decreased microbial diversity that may favor the development of atypical ocular infections [28]; and side effects of various different therapeutic approaches, such as contact lens wear or topical and systemic drugs [6; 7].