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Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease

Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease

Immunity 38(3): 450-460

Sj gren 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 I?B-? developed SS-like inflammation characterized by lymphocyte-infiltrated dacryoadenitis and SS-associated autoantibodies. In particular, epithelial cells, but not hematopoietic cells, lacking I?B-? were essential for the development of inflammation. I?B-?-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 I?B-? 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 I?B-? induction elicits the activation of self-reactive lymphocytes. I?B-?-deficient mice spontaneously develop an SS-like autoimmune disease I?B-? deficiency in hematopoietic cells is not essential for SS-like inflammation I?B-?-deficient epithelial cells accelerate apoptosis even without lymphocytes Accelerated apoptosis is crucial for the development of SS-like inflammation.

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Accession: 052982180

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PMID: 23453632

DOI: 10.1016/j.immuni.2012.11.016

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