Tanaka, TsutomuDiniz, Maria Cambraia GuimaroNakamura, HiroyukiPerez, PaolaJi, YoungmiMichael, Drew G.Afione, Sandra A.Zheng, ChangyuGoldsmith, CorinneSwaim, William D.Pedersen, Anne Marie LyngeChiorini, John A.2023-10-232023-10-232023-01-18Tanaka, Tsutomu, Maria C. Guimaro, Hiroyuki Nakamura, Paola Perez, Youngmi Ji, Drew G. Michael, Sandra A. Afione, et al. “Association of G Protein-Coupled Receptor 78 with Salivary Dysfunction in Male Sjögren’s Patients.” Oral Diseases n/a, no. n/a. Accessed October 17, 2023. https://doi.org/10.1111/odi.14506.https://doi.org/10.1111/odi.14506http://hdl.handle.net/11603/30334Objective: Sjögren's disease (SjD) has a strong sex bias, suggesting an association with sex hormones. Male SjD represents a distinct subset of the disease, but the pathogenic mechanisms of male SjD is poorly characterized. The aim of this study is to identify initiating events related to the development of gland hypofunction and autoimmunity in male SjD patients. Materials and methods: Human minor salivary glands were transcriptomically analyzed with microarrays to detect differentially expressed genes in male SjD patients. Identified genes were tested on their involvement in the disease using conditional transgenic mice and gene-overexpressing cells. Results: GPR78, an orphan G protein–coupled receptor, was overexpressed in the salivary glands of male SjD patients compared with male healthy controls and female SjD patients. Male GPR78 transgenic mice developed salivary gland hypofunction with increased epithelial apoptosis, which was not seen in control or female transgenic mice. In cell culture, GPR78 overexpression decreased lysosomal integrity, leading to caspase-dependent apoptotic cell death. GPR78-induced cell death in vitro was inhibited by treatment with estradiol. Conclusion: GPR78 overexpression can induce apoptosis and salivary gland hypofunction in male mice through lysosomal dysfunction and increased caspase-dependent apoptosis in salivary gland epithelium, which may drive disease in humans.10 pagesen-USThis work was written as part of one of the author's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.Public Domain Mark 1.0http://creativecommons.org/publicdomain/mark/1.0/Text