Immunotherapeutic targets in estrogen deficiency-dependent Sjögren's syndrome-related manifestations.
Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Previously, we found that tissue-specific apoptosis in the exocrine glands in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy. We found that RbAp48 overexpression induces p53-mediated apoptosis in the exocrine glands depending on estrogen deficiency. RbAp48-inducible transfectants result in rapid apoptosis with p53 phosphorylation (Ser9), and alpha-fodrin cleavage. Indeed, transgenic expression of the RbAp48 gene induced apoptosis in the exocrine glands, resulting in the development of autoimmune exocrinopathy resembling Sjögren's syndrome (SS). CD4(+) T-cell-mediated autoimmune lesions were aggravated with age, in association with production of autoantibodies against SS-A, SS-B and alpha-fodrin. These findings demonstrated that estrogen deficiency initiates tissue-specific apoptosis in the exocrine gland cells through RbAp48 overexpression and exerts a possible gender-based risk of autoimmune exocrinopathy in postmenopausal women. Thus, these data indicate RbAp48 to be a novel immunotherapeutic target for preventing epithelial cell apoptosis and the development of gender-based autoimmune exocrinopathy.
Arakaki
Rieko
R
Department of Oral Molecular Pathology, Institute of Health Bioscencse, The University of Tokushima Graduate School, 3 Kuramotocho, Tokushima 770-8504, Japan.
Ishimaru
Naozumi
N
Hayashi
Yoshio
Y
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D056505:Retinoblastoma-Binding Protein 4 / Q000235:genetics / Q000378:metabolism*; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012859:Sjogren's Syndrome / Q000276:immunology / Q000378:metabolism / Q000628:therapy*
D004967:Estrogens; D056505:Retinoblastoma-Binding Protein 4