{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:49:54Z","timestamp":1783421394547,"version":"3.54.6"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T00:00:00Z","timestamp":1488326400000},"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":[[2017,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Rheumatoid arthritis is an autoimmune disorder that affects the joints and other organs. Pulmonary complications contribute significantly to rheumatoid arthritis mortality. Retinoic acid and its synthetic compound AM80 play roles in immunoregulation but their effect on mucosal autoimmunity remains largely unknown. T follicular helper (Tfh) and Th17 cells are known to promote inflammation and autoantibody production. Using the K\/BxN autoimmune arthritis model, we elucidate a novel mechanism whereby oral AM80 administration suppressed lung mucosa\u2013associated Tfh and autoantibody responses by increasing the gut-homing \u03b14\u03b27 integrin expression on Tfh cells. This diverted Tfh cells from systemic (non-gut) inflamed sites such as the lung into the gut-associated lymphoid tissues, Peyer\u2019s patches, and thus reduced the systemic autoantibodies. AM80 also inhibited the lung Th17 response. AM80\u2019s effect in the lungs was readily applied to the joints as AM80 also inhibited Tfh and Th17 responses in the spleen, the major autoantibody producing site known to correlate with K\/BxN arthritis severity. Finally, we used anti-\u03b27 treatment as an alternative approach, demonstrating that manipulating T cell migration between the gut and systemic sites alters the systemic disease outcome. The \u03b27 blockade prevented both Tfh and Th17 cells from entering the non-immunopathogenic site, the gut, and retained these T effector cells in the systemic sites, leading to augmented arthritis. These data suggest a dual beneficial effect of AM80, targeting both Tfh and Th17 cells, and warrant strict safety monitoring of gut-homing perturbing agents used in treating intestinal inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1601776","type":"journal-article","created":{"date-parts":[[2017,1,28]],"date-time":"2017-01-28T02:30:39Z","timestamp":1485570639000},"page":"1855-1864","source":"Crossref","is-referenced-by-count":31,"title":["Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses"],"prefix":"10.1093","volume":"198","author":[{"given":"Debdut","family":"Naskar","sequence":"first","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krysta M","family":"Felix","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Pierce","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Jung Joyce","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719"},{"name":"Arizona Arthritis Center, College of Medicine, University of Arizona , Tucson, AZ 85719"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,3,1]]},"reference":[{"key":"2025031312200770200_r1","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1164\/ajrccm.156.2.9609016","article-title":"Interstitial lung disease in recent onset rheumatoid arthritis","volume":"156","author":"Gabbay","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025031312200770200_r2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1136\/thx.56.8.622","article-title":"Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests","volume":"56","author":"Dawson","year":"2001","journal-title":"Thorax"},{"key":"2025031312200770200_r3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1093\/rheumatology\/kel253","article-title":"Mortality in rheumatoid arthritis. 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Immunol."},{"key":"2025031312200770200_r35","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/nature10228","article-title":"Control of TH17 cells occurs in the small intestine","volume":"475","author":"Esplugues","year":"2011","journal-title":"Nature"},{"key":"2025031312200770200_r36","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ni.2416","article-title":"Induction and molecular signature of pathogenic TH17 cells","volume":"13","author":"Lee","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025031312200770200_r37","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/nature09447","article-title":"Generation of pathogenic T(H)17 cells in the absence of TGF-\u03b2 signalling","volume":"467","author":"Ghoreschi","year":"2010","journal-title":"Nature"},{"key":"2025031312200770200_r38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev-immunol-041015-055605","article-title":"Follicular helper T cells","volume":"34","author":"Vinuesa","year":"2016","journal-title":"Annu. Rev. Immunol."},{"key":"2025031312200770200_r39","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/sj.embor.7400361","article-title":"Semi-rational engineering of a coral fluorescent protein into an efficient highlighter","volume":"6","author":"Tsutsui","year":"2005","journal-title":"EMBO Rep."},{"key":"2025031312200770200_r40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1471-213X-9-49","article-title":"Use of KikGR a photoconvertible green-to-red fluorescent protein for cell labeling and lineage analysis in ES cells and mouse embryos","volume":"9","author":"Nowotschin","year":"2009","journal-title":"BMC Dev. Biol."},{"key":"2025031312200770200_r41","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0167-5699(92)90158-4","article-title":"The role of nasopharyngeal lymphoid tissue","volume":"13","author":"Kuper","year":"1992","journal-title":"Immunol. Today"},{"key":"2025031312200770200_r42","doi-asserted-by":"crossref","first-page":"836","DOI":"10.2174\/156652409789105525","article-title":"Role of beta7 integrins in intestinal lymphocyte homing and retention","volume":"9","author":"Gorfu","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"2025031312200770200_r43","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nri2637","article-title":"Dysregulation of germinal centres in autoimmune disease","volume":"9","author":"Vinuesa","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025031312200770200_r44","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrd2085","article-title":"B cells move to centre stage: novel opportunities for autoimmune disease treatment","volume":"5","author":"Browning","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025031312200770200_r45","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1145697","article-title":"Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid","volume":"317","author":"Mucida","year":"2007","journal-title":"Science"},{"key":"2025031312200770200_r46","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-pathol-011110-130318","article-title":"The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin","volume":"8","author":"Weaver","year":"2013","journal-title":"Annu. Rev. Pathol."},{"key":"2025031312200770200_r47","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.4049\/jimmunol.0902944","article-title":"Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid","volume":"184","author":"Cha","year":"2010","journal-title":"J. Immunol."},{"key":"2025031312200770200_r48","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1084\/jem.20070602","article-title":"Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid","volume":"204","author":"Sun","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025031312200770200_r49","doi-asserted-by":"crossref","first-page":"a007294","DOI":"10.1101\/cshperspect.a007294","article-title":"Microbiota and autoimmunity","volume":"5","author":"Chervonsky","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2025031312200770200_r50","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1126\/science.1223490","article-title":"Interactions between the microbiota and the immune system","volume":"336","author":"Hooper","year":"2012","journal-title":"Science"},{"key":"2025031312200770200_r51","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4161\/gmic.19320","article-title":"The role of gut microbiota in immune homeostasis and autoimmunity","volume":"3","author":"Wu","year":"2012","journal-title":"Gut Microbes"},{"key":"2025031312200770200_r52","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nbt0314-205","article-title":"First integrin inhibitor since Tysabri nears approval for IBD","volume":"32","author":"Sheridan","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"2025031312200770200_r53","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1080\/003655201317097173","article-title":"Musculoskeletal manifestations in a population-based cohort of inflammatory bowel disease patients","volume":"36","author":"Salvarani","year":"2001","journal-title":"Scand. J. Gastroenterol."},{"key":"2025031312200770200_r54","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s10067-007-0797-5","article-title":"A cross-sectional study of 130 Brazilian patients with Crohn\u2019s disease and ulcerative colitis: analysis of articular and ophthalmologic manifestations","volume":"27","author":"Lanna","year":"2008","journal-title":"Clin. Rheumatol."},{"key":"2025031312200770200_r55","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.4049\/jimmunol.1202490","article-title":"Antagonizing the \u03b14\u03b21 integrin, but not \u03b14\u03b27, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis","volume":"190","author":"Haanstra","year":"2013","journal-title":"J. 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