title: Establishing PAX6 as a biomarker to detect early loss of ocular phenotype in human patients with Sjögren's syndrome.
abstract: OBJECTIVE
  Sjögren's syndrome (SS) is a common autoimmune disease that can cause aqueous-deficient dry eye and the aberrant differentiation of ocular mucosal epithelial cells toward a lineage that is pathologically keratinized and skin-like. PAX6 is the master regulator of corneal lineage commitment. Recently, we showed a functional role for PAX6 in preventing ocular surface damage induced by the proinflammatory cytokine, IL-1β, in a mouse model of SS. Here, we examine PAX6's potential as a clinical biomarker that predicts ocular surface disease in SS patients.
  
  
  METHODS
  Impression cytology specimens isolated from the bulbar conjunctiva of control (n = 43) and SS patients (n = 43) were used to evaluate the relative abundance of PAX6, IL-1β, and pathologic keratinization marker, small proline-rich protein (SPRR1B) by TaqMan qPCR. Transcript expression was examined relative to clinical data, including the ocular staining score (OSS), tear breakup time (TBUT), Schirmer tear test, serum autoantibody results, and the labial salivary gland focus score.
  
  
  RESULTS
  PAX6 expression was significantly reduced in SS patients (P = 0.010, Wilcoxon rank sum test), and highly correlated with OSS (Spearman ρ = 0.239, 95% CI 0.02-0.43; P = 0.027). The extent to which PAX6 predicted SPRR1B was largely dependent on IL-1β expression (R(2) = 0.28, P < 0.01) and elevated IL-1β predicted reduced TBUT (R(2) = 0.24, P = 0.035), low tear secretion (R(2) = 0.30, P = 0.011), and focus score (R(2) = 0.21, P = 0.002).
  
  
  CONCLUSIONS
  Downregulation of PAX6 in SS patients was highly associated with ocular surface damage and largely dependent on the level of inflammation. Restoration of PAX6 may provide a clinical approach to manage dry eye in SS patients.
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States Department of Ophthalmology, University of California San Francisco, San Francisco, California, United States Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Porco
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007638:Keratoconjunctivitis Sicca / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012859:Sjogren's Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D012313:RNA
keywords: PAX6; Sjögren's syndrome; dry eye; ocular surface; squamous metaplasia