Abstract
BackgroundThe orphan nuclear receptors retinoic acid-related receptor α and γt (RORα and RORγt) are critical in the development of T helper 17 (Th17) cells, and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. However, the pathological significance of RORα in primary Sjögren’s syndrome (pSS) remains to be elucidated. The present study was designed to clarify the significance of RORα in the pathogenesis of pSS.MethodsRORα expression in the labial salivary gland (LSG) was determined by immunohistochemical analysis using a quantitative scoring system in 34 patients with pSS. The correlation between RORα expression in LSGs and the focus score (FS) was determined, and Th17 and IL-17 receptor A (1L-17RA) levels in LSGs were determined. To investigate the effect of RORs and the therapeutic potential of targeting RORs in pSS, we administered SR1001, a selective RORα/γt inverse agonist, to non-obese diabetic (NOD) mice.ResultsThe expression of RORα was significantly increased in LSGs of patients with pSS and intensified with disease stage/FS, showing a similar increasing trend with IL-17A and IL-17RA. SR1001 significantly improved salivary gland secretory function and relieved sialadenitis in treated mice.ConclusionOur data reveal the importance of RORα in controlling pathologic lymphocytic infiltration of the salivary glands and suggest that RORα may be a druggable target in treating pSS.
Highlights
The orphan nuclear receptors retinoic acid-related receptor α and γt (RORα and Orphan nuclear receptors retinoic acid-related receptor γt (RORγt)) are critical in the development of T helper 17 (Th17) cells, and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity
Patients Orphan nuclear receptors retinoic acid-related receptor α (RORα) expression in labial salivary gland (LSG) was determined in 46 patients with sicca syndrome who were referred to our department
RORα expression increased with increasing focus score (FS) RORα expression was monitored in the LSGs of primary Sjögren’s syndrome (pSS) patients with different FS and this indicated that RORα expression increased with increasing FS (Fig. 2c), which might suggest its participation in the pathogenesis of pSS
Summary
The orphan nuclear receptors retinoic acid-related receptor α and γt (RORα and RORγt) are critical in the development of T helper 17 (Th17) cells, and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. The pathological significance of RORα in primary Sjögren’s syndrome (pSS) remains to be elucidated. The present study was designed to clarify the significance of RORα in the pathogenesis of pSS. Primary Sjögren’s syndrome (pSS) is a chronic, systemic autoimmune disease characterized by lymphocyte infiltration into exocrine glands, such as salivary and lacrimal glands. Focal lymphocytic sialadenitis is the characteristic histopathological feature of pSS. The pathogenesis of pSS is not yet clear. Immunohistochemical studies have shown that T helper 17 (Th17) cells are among the infiltrating lymphocytes in the labial
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