{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:13:02Z","timestamp":1759943582323,"version":"build-2065373602"},"reference-count":48,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2015,7,28]],"date-time":"2015-07-28T00:00:00Z","timestamp":1438041600000},"content-version":"vor","delay-in-days":88,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Research Program for Intractable Diseases from the Ministry of Health, Labor, and Welfare of Japan (Health and Labor Sciences Research Grant Program)"},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology, Japan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Autoreactive CD4+ T cells are involved in the pathogenesis of Sj\u00f6gren's syndrome (SS). The aim of the present study was to clarify the dominant T cell epitopes of M3 muscarinic acetylcholine receptor (M3R) and to establish a new antigen\u2010specific therapy for SS using an experimental mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Production of cytokines from M3R\u2010reactive CD4+ T cells, after culture with various M3R peptides, was analyzed by enzyme\u2010linked immunosorbent assay. Adoptive cell transfer was performed using splenocytes from M3R<jats:sup>\u2212\/\u2212<\/jats:sup> mice that were immunized with M3R peptides or phosphate buffered saline plus H37Ra as a control. Rag1<jats:sup>\u2212\/\u2212<\/jats:sup> mice were inoculated with the splenocytes and examined for the development of sialadenitis. Altered peptide ligands (APLs) of the T cell epitopes, with substitutions in amino acid residues at T cell receptor contact sites, were synthesized, and the ability of the APLs to suppress sialadenitis was evaluated. The mechanisms underlying such effects were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD4+ M3R\u2010reactive T cells produced interleukin\u201017 (IL\u201017) and interferon\u2010\u03b3 (IFN\u03b3) in response to the N\u2010terminal 1 (N1) and 1st extracellular loop peptides of M3R, and Rag1<jats:sup>\u2212\/\u2212<\/jats:sup> mice that received N1\u2010 and\/or 1st peptide\u2013immunized splenocytes developed sialadenitis. Among the designed APLs, N1\u2010APL7 (N\u2192S at amino acid 15) significantly suppressed IFN\u03b3 production in vitro, and also suppressed sialadenitis in vivo. Levels of early growth response 2 in CD4+ T cells from the cervical lymph nodes of N1\u2010APL7\u2013treated mice were significantly higher than those of control mice, and cell proliferation was reversed by administration of exogenous IL\u20102. Levels of the anergy\u2010related molecules itchy homolog E3 ubiquitin\u2010protein ligase, Casitas B\u2010lineage lymphoma b, gene related to anergy in lymphocytes, and Deltex\u20101 were significantly higher in CD4+ T cells cultured with N1\u2010APL7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The major T cell epitopes were from the N1 and 1st peptide regions. Moreover, N1\u2010APL7, selected as the antagonistic APL in vitro, also suppressed sialadenitis through the induction of anergy. This is a potentially useful strategy for regulating pathogenic T cell infiltration in SS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39163","type":"journal-article","created":{"date-parts":[[2015,4,17]],"date-time":"2015-04-17T11:02:43Z","timestamp":1429268563000},"page":"2213-2225","source":"Crossref","is-referenced-by-count":12,"title":["The Anergy Induction of M3 Muscarinic Acetylcholine Receptor\u2013Reactive CD4+ T Cells Suppresses Experimental Sialadenitis\u2010like Sj\u00f6gren's Syndrome"],"prefix":"10.1002","volume":"67","author":[{"given":"Hiromitsu","family":"Asashima","sequence":"first","affiliation":[{"name":"University of Tsukuba Tsukuba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroto","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"University of Tsukuba Tsukuba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"University of 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