title: Matriptase deletion initiates a Sjögren's syndrome-like disease in mice.
abstract: OBJECTIVE
  The objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model.
  
  
  METHODS
  Embryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers.
  
  
  RESULTS
  Embryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjögren's syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjögren's syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers.
  
  
  CONCLUSIONS
  Our findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland function [corrected] in the absence of inflammation while systemic deletion can induce a primary Sjögren's syndrome like phenotype with autoimmunity and loss of gland function.
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hongen
authors.initials: H
authors.lastname: Yin
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Kosa
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xibao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Swaim
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera-Perez
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Pasquale
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Chiorini
mesh_terms: D000328:Adult; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015551:Autoimmunity; D002463:Cell Membrane Permeability; D002465:Cell Movement; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007765:Lacrimal Apparatus / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D012859:Sjogren's Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000276:immunology / Q000473:pathology
chemical_list: D000974:Antibodies, Antinuclear; D062725:Tight Junction Proteins; D012697:Serine Endopeptidases; C485595:matriptase