Influence of sex hormones and genetic predisposition in Sjögren’s syndrome: A new clue to the immunopathogenesis of dry eye disease

Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration, destruction of lacrimal and salivary glands and the presence of serum autoantibodies. Most women that suffer from SS are post-menopausal however, not all post-menopausal women develop SS, suggesting that other factors, in addition to the decrease in ovarian hormones, are necessary for the development of SS. The purposes of this study were to investigate a) the time course of lymphocytic infiltration and apoptosis in the lacrimal gland after ovariectomy, b) if a predisposed genetic background for SS aggravates the effects of decreasing levels of sex hormones in the lacrimal glands and c) if physiological doses of estrogen or androgen prevent the effects observed after ovariectomy. Six weeks old mice that are genetically predisposed to SS (NOD.B10.H2b) and control (C57BL/10) mice were either sham operated, ovariectomized (OVX), OVX + 17β estradiol (E2) or OVX + Dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21 or 30 days after surgery and processed for immunohistochemistry to measure CD4+, CD8+ T cells, B220+ B cells, nuclear DNA degradation and cleaved caspase-3 activity. Quantification of the staining was done by light microscopy and Image Pro Plus software. The results of our study show that lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy. Moreover, removal of ovarian sex hormones accelerated these effects in the genetically predisposed animal and these effects were more severe and persistent compared to control animals. In addition, sex hormone replacement at physiological levels prevented these symptoms. The mechanisms by which decreased levels of sex hormones caused lymphocytic infiltration and apoptosis and the interaction of lack of sex hormones with the genetic elements remain to be elucidated.

► Ovariectomy accelerated the symptoms of Sjögren’s syndrome in the lacrimal gland.
► Lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy.
► These effects were more severe and persistent in the genetically predisposed mice.
► Sex hormones replacement at physiological levels prevented these effects.