Interleukin-1 as a Phenotypic Immunomodulator in Keratinizing Squamous Metaplasia of the Ocular Surface in Sjogren's Syndrome

Chronic inflammation of the ocular surface in Sjogren's syndrome (SS) is associated with a vision-threatening, phenotypic change of the ocular surface, which converts from a nonkeratinized, stratified squamous epithelium to a nonsecretory, keratinized epithelium. This pathological process is known as squamous metaplasia. Based on a significant correlation between ocular surface interleukin (IL)-1 beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in all animal model that mimics the clinical characteristics of SS. Using autoimmune-regulator (aire)deficient mice, we assessed lacrimal gland and ocular surface immunopathology by quantifying the infiltration of major histocompatibility complex class II+ (I-A(d+)) dendritic cells and CD4(+) T cells. We examined squamons metaplasia using a biomarker of keratinization, small proline-rich protein 1B. We used Lissamine green staining as a readout for ocular surface epitheliopathy and Alcian blue/periodic acid-Schiff histochemical analysis to characterize goblet cell muco-glycoconjugates. Within 8 weeks, the eyes of aire-deficient mice were pathologically keratinized with significant epithelial damage and altered mucin glycosylation. Although knockdown of IL-1 receptor 1 did not attenuate lymphocytic infiltration of the lacrimal gland or eye, it significantly reduced ocular surface keratinization, epitheliopathy, and muco-glycoconjugate acidification. These data demonstrate a phenotypic modulation role for IL-1 in the pathogenesis of squamous metaplasia and suggest that IL-1 receptor 1-targeted therapies may be beneficial for treating ocular surface disease associated with SS. (Am J Pathol 2010 177:1333-1343; DOI: 10.2353/ajpath.2010.100227)