Background/objective Sjögren’s Syndrome (SS) is a chronic autoimmune disorder that mainly affects the exocrine glands, with largely unknown initiation and causative agents. Endoplasmic Reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either by acting as autoantigens themselves, or by modulating factors in inflammatory responses. ERdj5 is an ER-resident chaperone protein with a disulfide reductase activity, required for the translocation of misfolded proteins across the ER for proteasomal degradation. In this study we sought to investigate the role of ERdj5 in the salivary glands, in association with inflammation and autoimmunity.
Methods In situ expression of ERdj5 was studied immunohistochemically in Minor Salivary Gland (MSG) tissues from primary SS-patients and non-SS sicca-complaining controls. Submaxillary glands and sera from both male and female ERdj5-knockout mice and age-matched wild types were collected at 6, 34 and 52 weeks of age. Tissue samples were analysed microscopically, while sera were screened for anti-nuclear antibodies (ANAs).
Results Human MSGs expressed ERdj5 with higher stain intensity in the MSGs of SS patients compared to non-SS sicca controls. Particularly, the intensity of expression was correlated with the grade of the inflammatory lesions. Mice deficient in ERdj5 spontaneously developed SS-like inflammation in submaxillary glands and ANAs systemically. Inflammation was characterised by B and T infiltrating lymphocytes. Notably, female ERdj5-knockout mice developed severe chronic periductal inflammation in contrast to the much milder phenotype found in male littermates.
Conclusions Salivary glands of ERdj5-knockout mice resemble the pathologic lesions of human Sjögren’s Syndrome, whereas ERdj5 was induced in MSGs of SS patients. Our findings suggest a critical connexion between the function of the ER stress chaperone protein ERdj5 and autoimmune inflammatory responses in the salivary glands.