We have demonstrated that conjunctival epithelium of SS patients displays increased numbers of S-phase cells compared with non-dry eye controls. Moreover, in SS patients, these S-phase cells are distributed throughout all strata of the epithelium. The expression of MUC-1, a cell surface marker indicative of terminally differentiated epithelium, is localized to the conjunctival epithelial surface in SS and control patients. However, MUC-1 surface immunoreactivity appears to be reduced in SS epithelium, suggesting disruption of normal epithelial differentiation. A MUC-1 epitope exposed by pretreatment with neuraminidase is expressed in the basal and suprabasal layers of both patient populations. This antigen likely represents nascent, partially processed MUC-1(6) and may serve as a marker of the preterminally differentiated epithelial phenotype. Messenger RNA encoding several different inflammatory cytokines, including TNF-alpha, IL-1 alpha and beta, IL-6, IL-8, IL-10, and TGF-beta 1, is expressed at elevated levels within the conjunctival epithelium of SS patients compared with non-dry eye controls. Based on these observations, we have formulated a model to explain the ocular surface pathology of Sjögren's syndrome. We hypothesize that mechanical abrasion secondary to aqueous tear deficiency creates an inflammatory environment where conjunctival epithelial cells and lymphocytes are stimulated to produce and secrete various cytokines (i.e., IL-1, TNF-alpha, IL-6, IL-8, etc.) into the tear film. Elevated cytokine levels within the tear film, perhaps combined with reduced concentrations of essential lacrimal gland-derived factors (i.e., EGF, retinol), create an environment in which terminal differentiation of the ocular surface epithelium is impaired. As a consequence, the epithelium becomes hyperplastic, displaying increased mitotic activity, and loses the ability to express mature protective surface molecules including the membrane-bound mucin, MUC-1. This would imply that anti-inflammatory medications (i.e., corticosteroids or cyclosporine) that suppress the inflammatory component of this cascade may ameliorate the ocular surface disease and discomfort experienced by SS patients.