Recent evidences suggest that the apoptotic pathway plays a central role in tolerazing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon in the salivary glands. We found that retinoblastoma-associated protein RbAp48 overexpression induces p53-mediated apoptosis in the salivary glands caused by estrogen deficiency. We demonstrated that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren’s syndrome (SS). CD4⁺T cell-mediated autoimmune lesions in the salivary glands were aggravated with age, in association with autoantibody productions. We obtained evidences that salivary epithelial cells can produce interferon-γ (IFN-γ) besides interleukin (IL)-18, which activates interferon regulatory factor-1 (IRF-1), and class II transactivator (CIITA). Indeed, the autoimmune lesions into Rag2^-/- mice were induced by the adoptive transfer of lymph node cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-γ, resulting in loss of local tolerance prior to developing gender-based autoimmunity. The studies reviewed the molecular mechanisms on the development of salivary gland autoimmunity, and gender-related differences in SS. J. Med. Invest. 56 Suppl.: 185-191, December, 2009