Development of autoimmune exocrinopathy resembling Sjögren's syndrome in estrogen-deficient mice of healthy background.
Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear. We speculate that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens. Previously, we have identified 120-kd alpha-fodrin as an important autoantigen in Sjögren's syndrome (SS). When healthy C57BL/6 (B6) mice were treated with an ovariectomy (Ovx), we found a significant increase in TUNEL(+)-apoptotic epithelial cells in the salivary gland cells associated with alpha-fodrin cleavage during 2 and 3 weeks after Ovx. By contrast, no apoptotic cells were found in estrogen receptor-alpha knockout mice. In in vitro studies using primary cultured mouse salivary gland cells and human salivary gland cells, we found a cleavage product of 120-kd alpha-fodrin in cells that had undergone tamoxifen (Tam)-induced apoptosis through caspase activation, especially caspase-1. Adoptive transfer of alpha-fodrin-reactive T cells into Ovx-B6 and -SCID mice resulted in the development of autoimmune exocrinopathy quite similar to SS. These results suggest that estrogen deficiency exerts a crucial influence on autoantigen cleavage, and may cause, in part, autoimmune exocrinopathy in postmenopausal women.
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D010052:Ovariectomy; D010447:Peptide Hydrolases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency; D012466:Salivary Gland Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D012469:Salivary Glands / Q000473:pathology / Q000503:physiopathology; D012859:Sjogren's Syndrome / Q000473:pathology / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000276:immunology; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D013049:Spectrin
D002352:Carrier Proteins; D020169:Caspases; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008840:Microfilament Proteins; D010447:Peptide Hydrolases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D013049:Spectrin