Estrogen Deficiency Accelerates Autoimmune Exocrinopathy in Murine Sjögren's Syndrome through Fas-Mediated Apoptosis

Abstract

Estrogenic action has been suggested to be responsible for the strong female preponderance of autoimmune diseases, but the role of estrogens in the female has not been well characterized. We evaluated the effects of estrogen deficiency in a murine model for autoimmune exocrinopathy of Sjögren's syndrome (SS). Severe destructive autoimmune lesions developed in the salivary and lacrimal glands in estrogen-deficient mice, and these lesions were recovered by estrogen administration. We detected an intense estrogen receptor in splenic CD8(+) T cells compared with that in CD4(+) T cells, and concanavalin-A-stimulated blastogenesis of splenic CD8(+) T cells with estrogens was much higher than that of CD4(+) T cells. We found a significant increase in serum autoantibody production against the organ-specific autoantigen alpha-fodrin. Moreover, an increased proportion of TUNEL+ apoptotic epithelial duct cells was observed in estrogen-deficient mice. It was demonstrated that Fas-mediated apoptosis in cultured salivary gland cells was clearly inhibited by estrogens in vitro. These results indicate that dysfunction of regulatory T cells by estrogen deficiency may play a crucial role on acceleration of organ-specific autoimmune lesions, and estrogenic action further influences target epithelial cells through Fas-mediated apoptosis in a murine model for SS.

Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands

“…Recent evidence suggests that apoptosis plays a key role in the physiology and pathogenesis of various autoimmune diseases (2,7,19,35,42). We have demonstrated that estrogenic action influences target epithelial cells through Fas-mediated apoptosis in a murine model for Sjögren's syndrome (13). Recently, we found that tissue-specific apoptosis in the exocrine glands spontaneously occurring in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy (14).…”

Effects of Diabetes on Post-Menopausal Rat Submandibular Glands: A Histopathological and Stereological Examination

“…In late-phase diabetes, an increase in the number of autophagic structures occurs in granular duct cells. The histological findings from non-obese diabetic mice's submandibular gland tissues also indicate damage accompanied by massive cell infiltration [28][29][30][31]. Some studies have shown that oestrogen and progesterone regulate the structure and function of the submandibular glands.…”

Role of Plasmacytoid Dendritic Cells for Aberrant Class II Expression in Exocrine Glands from Estrogen-Deficient Mice of Healthy Background

“…25,26 Previously, we demonstrated that estrogenic action influences target epithelial cells through Fas-mediated apoptosis in a murine model of SS. 27 Moreover, we found that the tissue-specific apoptosis in the exocrine glands spontaneously occurring in estrogen-deficient healthy C56BL/6 (B6) mice may contribute to the development of autoimmune exocrinopathy resembling SS. 28 Recently in minor salivary glands from patients with SS, significantly increased development of IFN pathways and increased plasmacytoid dendritic cells (pDCs) as a possible source of IFN were shown.…”

“…27,28 Briefly, mouse submandibular glands were minced into 1-mm 2 pieces, digested with collagenase (750 U/ml of type I) and hyarulonidase (500 U/ml of type IV) in Dulbecco's modified Eagle's medium containing 10% fetal calf serum. The digested suspension was passed through a 75-m nylon mesh filter.…”