Disruption of tight junction structure in salivary glands from Sjögren's syndrome patients is linked to proinflammatory cytokine exposure

Arthritis Rheum. 2010 May;62(5):1280-9. doi: 10.1002/art.27362.

Abstract

Objective: Disorganization of acinar cell apical microvilli and the presence of stromal collagen in the acinar lumen suggest that the labial salivary gland (LSG) barrier function is impaired in patients with Sjögren's syndrome. Tight junctions define cell polarity and regulate the paracellular flow of ions and water, crucial functions of acinar cells. This study was undertaken to evaluate the expression and localization of tight junction proteins in LSGs from patients with SS and to determine in vitro the effects of tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma) on tight junction integrity of isolated acini from control subjects.

Methods: Twenty-two patients and 15 controls were studied. The messenger RNA and protein levels of tight junction components (claudin-1, claudin-3, claudin-4, occludin, and ZO-1) were determined by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting. Tight junction protein localization was determined by immunohistochemistry. Tight junction ultrastructure was examined by transmission electron microscopy. Isolated acini from control subjects were treated with TNFalpha and IFNgamma.

Results: Significant differences in tight junction protein levels were detected in patients with SS. ZO-1 and occludin were strongly down-regulated, while claudin-1 and claudin-4 were overexpressed. Tight junction proteins localized exclusively to apical domains in acini and ducts of LSGs from controls. In SS patients, the ZO-1 and occludin the apical domain presence of decreased, while claudin-3 and claudin-4 was redistributed to the basolateral plasma membrane. Exposure of isolated control acini to TNFalpha and IFNgamma reproduced these alterations in vitro. Ultrastructural analysis associated tight junction disorganization with the presence of endocytic vesicles containing electron-dense material that may represent tight junction components.

Conclusion: Our findings indicate that local cytokine production in LSGs from SS patients may contribute to the secretory gland dysfunction observed in SS patients by altering tight junction integrity of epithelial cells, thereby decreasing the quality and quantity of saliva.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Claudin-1
  • Claudin-3
  • Claudin-4
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Interferon-gamma / immunology*
  • Interferon-gamma / pharmacology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microscopy, Electron, Transmission
  • Middle Aged
  • Occludin
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA, Messenger / metabolism
  • Salivary Glands / immunology*
  • Salivary Glands / pathology
  • Sjogren's Syndrome / immunology*
  • Sjogren's Syndrome / metabolism
  • Sjogren's Syndrome / pathology
  • Tight Junctions / immunology*
  • Tight Junctions / pathology
  • Tight Junctions / ultrastructure
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Zonula Occludens-1 Protein

Substances

  • CLDN1 protein, human
  • CLDN3 protein, human
  • CLDN4 protein, human
  • Claudin-1
  • Claudin-3
  • Claudin-4
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • Phosphoproteins
  • RNA, Messenger
  • TJP1 protein, human
  • Tumor Necrosis Factor-alpha
  • Zonula Occludens-1 Protein
  • Interferon-gamma