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The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradation products such as nucleosides and oligoribonucleotides, the role of these ligands in sialadenitis development remains unclear. Here, we demonstrate that lysosomal accumulation of endogenous nucleosides is sufficient to drive autoimmune sialadenitis. Loss-of-function genetic variations in the nucleoside transporter SLC29A3 cause lysosomal nucleoside accumulation, leading to constitutive activation of TLR7 and TLR8 in monocytes and macrophages. Consequently, macrophages infiltrate multiple organs in mice and humans. In Slc29a3\u2212\/\u2212 mice, submandibular glands (SMGs) were impaired in saliva production. SLC29A3-deficiency specifically damaged Aqp5+ acinar and intercalated duct cells in SMGs, while sparing neighboring cells such as ductal and myoepithelial cells. Although macrophages accumulated in both the spleen and SMGs, lymphocyte infiltration and production of chemokines, including CXCL9, CXCL13, and CCL5, occurred selectively in SMGs. In IgG4-RD patients, these chemokines were also produced in SMGs, highlighting parallels between sialadenitis in Slc29a3\u2212\/\u2212 mice and IgG4-RD. These findings indicate that constitutive TLR7 activation by nucleosides is a key mechanism driving autoimmune sialadenitis.<\/jats:p>","DOI":"10.1093\/intimm\/dxaf073","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:48:20Z","timestamp":1764679700000},"page":"306-317","source":"Crossref","is-referenced-by-count":3,"title":["TLR7 responses to nucleosides drive sialadenitis in Slc29a3-deficient mice"],"prefix":"10.1093","volume":"38","author":[{"given":"Takuma","family":"Shibata","sequence":"first","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Division of Aging and Regeneration, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotono","family":"Okabe-Kibe","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University , Fukuoka 812-8582 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University , Fukuoka 812-8582 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo , Minato-ku, Tokyo 108-8639 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University , Asahikawa, Hokkaido 078-8510 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-4951","authenticated-orcid":false,"given":"Masato","family":"Taoka","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University , Tokyo 192-0397 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Motoi","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University , Chiba 260-8670 ,","place":["Japan"]},{"name":"Medical Mycology Research Center, Chiba University , Chiba 260-8673 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University , Chiba 260-8670 ,","place":["Japan"]},{"name":"Medical Mycology Research Center, Chiba University , Chiba 260-8673 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Wen","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Division of Aging and Regeneration, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryutaro","family":"Fukui","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University , Chiba 260-8670 ,","place":["Japan"]},{"name":"Medical Mycology Research Center, Chiba University , Chiba 260-8673 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University , Fukuoka 812-8582 ,","place":["Japan"]},{"name":"OBT Research Center, Faculty of Dental Science, Kyushu University , Fukuoka 812-8582 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqin","family":"Wang","sequence":"additional","affiliation":[{"name":"The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University , Tianjin 300070 ,","place":["China"]},{"name":"National Key Laboratory of Blood Science , Tianjin 300020 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tianjin Medical University General Hospital , Tianjin 300052 ,","place":["China"]},{"name":"Tianjin Clinical Research Center for Rheumatic and Immune Diseases , Tianjin 300052 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,","place":["China"]},{"name":"Department of Rheumatology and Immunology, Tianjin Medical University General Hospital , Tianjin 300052 ,","place":["China"]},{"name":"Department of Hematology, Tianjin Medical University General Hospital , Tianjin 300052 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo , Minato-ku, Tokyo 108-8639 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"K. 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