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In addition, recent studies have implicated the Toll\u2010like receptor (\n TLR<\/jats:styled-content>\n ) pathway. This study was undertaken to examine the expression of\n TLR<\/jats:styled-content>\n s in salivary glands (\n SG<\/jats:styled-content>\n s) from patients with IgG4\u2010\n RD<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n SG<\/jats:styled-content>\n s from 15 patients with IgG4\u2010\n RD<\/jats:styled-content>\n , 15 patients with Sj\u00f6gren's syndrome (\n SS<\/jats:styled-content>\n ), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically.\n TLR<\/jats:styled-content>\n family gene expression (\n TLR<\/jats:styled-content>\n \u20101 through\n TLR<\/jats:styled-content>\n \u201010) was analyzed by\n DNA<\/jats:styled-content>\n microarray in the submandibular glands (\n SMG<\/jats:styled-content>\n s). Up\u2010regulation of\n TLR<\/jats:styled-content>\n s was confirmed in\n SG<\/jats:styled-content>\n s from patients with IgG4\u2010\n RD<\/jats:styled-content>\n . Finally, the phenotype of human\n TLR<\/jats:styled-content>\n \u20107 (hu\n TLR<\/jats:styled-content>\n \u20107)\u2013transgenic C57\n BL<\/jats:styled-content>\n \/6 mice was assessed before and after stimulation with\n TLR<\/jats:styled-content>\n agonist.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In patients with IgG4\u2010\n RD<\/jats:styled-content>\n ,\n TLR<\/jats:styled-content>\n \u20104,\n TLR<\/jats:styled-content>\n \u20107,\n TLR<\/jats:styled-content>\n \u20108, and\n TLR<\/jats:styled-content>\n \u20109 were overexpressed. Polymerase chain reaction validated the up\u2010regulation of\n TLR<\/jats:styled-content>\n \u20107 in IgG4\u2010\n RD<\/jats:styled-content>\n compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of\n TLR<\/jats:styled-content>\n \u20107\u2013positive cells in the\n SG<\/jats:styled-content>\n s of patients with IgG4\u2010\n RD<\/jats:styled-content>\n . Double immunohistochemical staining showed that\n TLR<\/jats:styled-content>\n \u20107 expression colocalized with\n CD<\/jats:styled-content>\n 163+ M2 macrophages. After in vitro stimulation with a\n TLR<\/jats:styled-content>\n \u20107 agonist,\n CD<\/jats:styled-content>\n 163+ M2 macrophages produced higher levels of interleukin\u201033 (\n IL<\/jats:styled-content>\n \u201033), which is a Th2\u2010activating cytokine. In hu\n TLR<\/jats:styled-content>\n \u20107\u2013transgenic mice, the focus and fibrosis scores in\n SMG<\/jats:styled-content>\n s, pancreas, and lungs were significantly higher than those in wild\u2010type mice (\n P<\/jats:italic>\n < 0.05). Moreover, the concentration of serum IgG, IgG1, and\n IL<\/jats:styled-content>\n \u201033 in hu\n TLR<\/jats:styled-content>\n \u20107\u2013transgenic mice was distinctly increased upon stimulation with a\n TLR<\/jats:styled-content>\n \u20107 agonist (\n P<\/jats:italic>\n < 0.05).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n TLR<\/jats:styled-content>\n \u20107\u2013expressing M2 macrophages may promote the activation of Th2 immune responses via\n IL<\/jats:styled-content>\n \u201033 secretion in IgG4\u2010\n RD<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41052","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T02:25:13Z","timestamp":1563935113000},"page":"166-178","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Activated M2 Macrophages Contribute to the Pathogenesis of IgG4\u2010Related Disease via Toll\u2010like Receptor 7\/Interleukin\u201033 Signaling"],"prefix":"10.1002","volume":"72","author":[{"given":"Noriko","family":"Ishiguro","sequence":"first","affiliation":[{"name":"Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-2244","authenticated-orcid":false,"given":"Masafumi","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiro","family":"Furusho","sequence":"additional","affiliation":[{"name":"Kyushu University, Fukuoka, Japan, and University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Shibata","sequence":"additional","affiliation":[{"name":"University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Murakami","sequence":"additional","affiliation":[{"name":"University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Chinju","sequence":"additional","affiliation":[{"name":"Kyushu University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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