Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren's syndrome through Fas-mediated apoptosis

Estrogenic action has been suggested to be responsible for the strong femal e preponderance of autoimmune diseases, but the role of estrogens In the fe male has not been well characterized. We evaluated the effects of estrogen deficiency in a murine model for autoimmune exocrinopathy of Sjogren's synd rome (SS). Severe destructive autoimmune lesions developed in the salivary and lacrimal glands in estrogen-deficient mice, and these lesions were reco vered by estrogen administration. We detected an intense estrogen receptor in splenic CD8(+) T cells compared with that in CD4(+) T cells, and concana valin-A-stimulated blastogenesis of splenic CD8(+) T cells with estrogens w as much higher than that of CD4(+) T cells. We found a significant increase in serum autoantibody production against the organ-specific autoantigen al pha-fodrin. Moreover, an increased proportion of TUNEL+ apoptotic epithelia l duct cells was observed in estrogen-deficient mice. It was demonstrated t hat Fas-mediated apoptosis In cultured salivary gland cells was clearly inh ibited by estrogens in vitro. These results indicate that dysfunction of re gulatory T cells by estrogen deficiency may play a crucial role on accelera tion of organ-specific autoimmune lesions, and estrogenic action further in fluences target epithelial cells through Fas-mediated apoptosis in a murine model for SS.