Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjögren's syndrome

Am J Pathol. 2010 Sep;177(3):1333-43. doi: 10.2353/ajpath.2010.100227. Epub 2010 Aug 9.


Chronic inflammation of the ocular surface in Sjögren'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)-1beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in an 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 squamous 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Count
  • Eye / immunology
  • Eye / metabolism
  • Eye / pathology*
  • Eye Diseases / immunology*
  • Eye Diseases / metabolism
  • Eye Diseases / pathology
  • Humans
  • Immunohistochemistry
  • Interleukin-1 / immunology*
  • Interleukin-1 / metabolism
  • Metaplasia / immunology
  • Metaplasia / metabolism
  • Metaplasia / pathology
  • Mice
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sjogren's Syndrome / immunology*
  • Sjogren's Syndrome / metabolism
  • Sjogren's Syndrome / pathology


  • Interleukin-1