{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T18:44:40Z","timestamp":1759776280106,"version":"3.38.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17\u2013producing \u03b1\u03b2+\u03b3\u03b4\u2212 conventional CD4+ T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT\u2013HVEM and BTLA\u2013HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.<\/jats:p>","DOI":"10.4049\/jimmunol.1501742","type":"journal-article","created":{"date-parts":[[2016,2,25]],"date-time":"2016-02-25T04:31:58Z","timestamp":1456374718000},"page":"2947-2954","source":"Crossref","is-referenced-by-count":13,"title":["Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses"],"prefix":"10.1093","volume":"196","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1519-893X","authenticated-orcid":false,"given":"Yukimi","family":"Sakoda","sequence":"first","affiliation":[{"name":"Department of Immunology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiko","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Immunology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]},{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sizuka","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukari","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"Department of Immunology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Shoda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoyuki","family":"Morishige","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoji","family":"Yanai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koh-Hei","family":"Sonoda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Tamada","sequence":"additional","affiliation":[{"name":"Department of Immunology, Yamaguchi University Graduate School of Medicine , Ube City, Yamaguchi 755-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"2025030702151547500_r1","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1136\/bjo.80.9.844","article-title":"The possible impact of uveitis in blindness: a literature survey","volume":"80","author":"Suttorp-Schulten","year":"1996","journal-title":"Br. 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Rare Dis."},{"key":"2025030702151547500_r5","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3109\/08820538.2014.959203","article-title":"Side-effects of anti-inflammatory therapy in uveitis","volume":"29","author":"Uchiyama","year":"2014","journal-title":"Semin. Ophthalmol."},{"key":"2025030702151547500_r6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/0301-4738.58466","article-title":"Treatment of uveitis: beyond steroids","volume":"58","author":"Sangwan","year":"2010","journal-title":"Indian J. Ophthalmol."},{"key":"2025030702151547500_r7","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.4049\/jimmunol.140.5.1490","article-title":"A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens","volume":"140","author":"Caspi","year":"1988","journal-title":"J. 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