Although it has been well documented that aberrant major histocompatibility complex class II molecules may contribute to the development of autoimmune disorders, the precise mechanisms responsible for their tissue-specific expression remain unknown. Here we show that estrogen deficiency induces aberrant class II major histocompatibility complex expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells. Relatively modest but functionally significant expression levels of major histocompatibility complex class II and class II transactivator molecules were observed in the exocrine glands of ovariectomized (Ovx) C57BL/6 (B6) mice, but were not seen in the exocrine glands of control B6 mice. We observed that the salivary dendritic cells adjacent to the apoptotic epithelial cells positive for terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling, were activated in Ovx mice, but were not activated in control mice. We obtained evidence that the salivary gland cells express both interferon regulatory factor-1 and class II transactivator type IV molecules in Ovx mice. Major histocompatibility complex (MHC) class II molecules are crucial for restricting immune reactivity to self versus foreign antigens during thymic education, and their expression level is essential for determining T cell activation in the periphery.1-3 MHC class II molecules are basically expressed on antigen (Ag)-presenting cells of the hematopoietic lineage, but can be induced by unknown stimuli on many other cell types (such as endothelial cells, hepatocytes, pancreatic ␤-cells, thyrocytes, and salivary gland cells) in association with autoimmunity.4 -10 MHC class II proteins play a central role in the control of normal immune homeostasis, while aberrant expression of MHC class II is frequently associated with abnormalities in immune responses.11-13 MHC class II expression is regulated by multiple cytokines, including interferon (IFN)-␥, which can enhance the immune response by upregulating MHC class II expression in immune cells, in addition to inducing Ag-presentation capacity.14,15 It is well known that the induction of MHC class II gene transcription by IFN-␥ is mediated by the MHC class II transactivator (CIITA), and depends on the presence of two transcription factors; signal transducer and activator of transcription 1 and interferon regulatory factor (IRF-1). 16 CIITA is a true co-activator because it does not bind directly to DNA but mediates its function on the class II MHC promoter through interaction with other proteins. 17,18 It is considered a master regulator because it is necessary and sufficient for the expression of all of the genes in the MHC class II pathway. Although recent studies have begun to reveal that epigenetic mechanisms have a key role in activating CIITA expression in normal cells, 19 the factors regulating this promoter have yet to be investigated.