Sjögren's syndrome-like autoimmune sialadenitis in MRL-Fas^lpr mice is associated with expression of glucocorticoid-induced TNF receptor-related protein (GITR) ligand and 4-1BB ligand

Abstract

Although costimulatory molecules have been shown to play crucial roles in the immune response, their involvement in the pathogenesis of Sjögren's syndrome is incompletely understood. In this study, we evaluated the relationship between the severity of spontaneous Sjögren's syndrome-like autoimmune sialadenitis in MRL/MpJ-lpr/lpr (MRL-Fas^lpr) mice and the expression of 6 costimulatory molecules that play important roles in the immune response: CD80, CD86, OX40 ligand (OX40L), 4-1BB ligand (4-1BBL), glucocorticoid-induced TNF receptor-related protein ligand (GITRL), and B cell-activating factor of the tumor necrosis factor family (BAFF). Expression of the costimulatory molecules in the submandibular salivary glands of age-matched autoimmune MRL-Fas^lpr mice and non-autoimmune MRL/MpJ-+/+(MRL/+) and C3H/HeJ-lpr/lpr (C3H-Fas^lpr) mice was examined immunohistochemically and scored on a scale of 0 to 3. The severity of sialadenitis was evaluated histologically and scored on a scale of 0 to 3. We found that all of the costimulatory molecules were expressed in duct epithelial cells of salivary glands from MRL-Fas^lpr mice, whereas immunoreactivity was absent or weak in the MRL/+ mice. The staining intensity for all 6 costimulatory molecules was significantly higher in the MRL-Fas^lpr than in the MRL/+ mice. Partial correlation analysis was performed to assess the degree of association between costimulatory molecule staining scores and disease scores, which clearly revealed a significant correlation for only GITRL and 4-1BBL. These molecules showed negligible immunoreactivity in the submandibular glands of C3H-Fas^lpr mice, suggesting that their expression was independent of the Fas^lpr mutation. In conclusion, the expression of GITRL and 4-1BBL in salivary gland duct epithelial cells is associated with background genes in the MRL strain, but not with the Fas^lpr mutation itself, and contributes significantly to the pathogenesis of autoimmune sialadenitis in MRL-Fas^lpr mice. These results suggest that GITRL and 4-1BBL may be effective targets for the development of therapies for Sjögren's syndrome.

Keywords::

• CD80
• CD86
• OX40L
• BAFF
• MRL-Fas^lpr mice

Acknowledgements

We are grateful to Dr Masato Nose for his helpful suggestions throughout this study.

Declaration of interest: This work was supported by Grants-in-Aid for Scientific Research (C) (No. 1792175) provided by the Japan Society for the Promotion of Science. The authors declare no conflicts of interest associated with the manuscript. The authors are responsible for the content and writing of this paper.