ABSTRACT
Sjögren's syndrome (SS) is an autoimmune disease characterized by exocrinopathy that leads to dry eye and mouth. Although lymphocyte infiltration into exocrine glands and the generation of autoantibodies have been reported in SS, its pathogenic mechanism remains elusive. Here, we show that mice lacking the transcriptional regulator IκB-ζ developed SS-like inflammation characterized by lymphocyte-infiltrated dacryoadenitis and SS-associated autoantibodies. In particular, epithelial cells, but not hematopoietic cells, lacking IκB-ζ were essential for the development of inflammation. IκB-ζ-deficient epithelial cells in the lacrimal glands exhibited enhanced apoptosis even in the absence of lymphocytes. Administration of caspase inhibitors ameliorated the inflammation, indicating the critical role of caspase-mediated apoptosis. Furthermore, epithelial cell-specific STAT3-deficient mice developed SS-like inflammation with impaired IκB-ζ expression in the lacrimal glands. Thus, this study reveals a pathogenic mechanism of SS in which dysfunction of epithelial cells caused by disruption of STAT3-mediated IκB-ζ induction elicits the activation of self-reactive lymphocytes.
Subject(s)
Apoptosis/immunology , Autoimmune Diseases/immunology , Epithelial Cells/immunology , STAT3 Transcription Factor/immunology , Sjogren's Syndrome/immunology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Animals , Apoptosis/genetics , Autoimmune Diseases/genetics , Autoimmune Diseases/metabolism , Epithelial Cells/metabolism , Female , Immunohistochemistry , In Situ Nick-End Labeling , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Lacrimal Apparatus/immunology , Lacrimal Apparatus/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/immunology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , Sjogren's Syndrome/genetics , Sjogren's Syndrome/metabolismABSTRACT
We describe a 75-year-old Japanese woman with blastic plasmacytoid dendritic cell neoplasm. On her first visit, there were multiple areas of disseminated, elastic hard nodules with multicentric purpura on her scalp. Histopathologically, there were atypical large lymphocytes densely infiltrated through the upper dermis to subcutaneous tissue. Immunohistochemical staining revealed that these infiltrated lymphocytes were CD4, CD56 and vimentin positive. Although we administered several courses of intensive chemotherapy soon after the diagnosis, the patient died 5 months after the first visit.
