{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:35:26Z","timestamp":1791279326613,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2010,8,1]],"date-time":"2010-08-01T00:00:00Z","timestamp":1280620800000},"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":[[2010,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Rheumatoid arthritis (RA) is closely associated with HLA-DRB1 alleles that code a five-amino acid sequence motif in positions 70\u201374 of the HLA-DR\u03b2\u2013chain, called the shared epitope (SE). The mechanistic basis of SE\u2013RA association is unknown. We recently found that the SE functions as an allele-specific signal-transducing ligand that activates an NO-mediated pathway in other cells. To better understand the role of the SE in the immune system, we examined its effect on T cell polarization in mice. In CD11c+CD8+ dendritic cells (DCs), the SE inhibited the enzymatic activity of indoleamine 2,3 dioxygenase, a key enzyme in immune tolerance and T cell regulation, whereas in CD11c+CD8\u2212 DCs, the ligand activated robust production of IL-6. When SE-activated DCs were cocultured with CD4+ T cells, the differentiation of Foxp3+ T regulatory cells was suppressed, whereas Th17 cells were expanded. The polarizing effects could be seen with SE+ synthetic peptides, but even more so when the SE was in its natural tridimensional conformation as part of HLA-DR tetrameric proteins. In vivo administration of the SE ligand resulted in a greater abundance of Th17 cells in the draining lymph nodes and increased IL-17 production by splenocytes. Thus, we conclude that the SE acts as a potent immune-stimulatory ligand that can polarize T cell differentiation toward Th17 cells, a T cell subset that was recently implicated in the pathogenesis of autoimmune diseases, including RA.<\/jats:p>","DOI":"10.4049\/jimmunol.0904002","type":"journal-article","created":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T03:07:48Z","timestamp":1277953668000},"page":"1927-1934","source":"Crossref","is-referenced-by-count":49,"title":["Immune Dysregulation by the Rheumatoid Arthritis Shared Epitope"],"prefix":"10.1093","volume":"185","author":[{"given":"Denise E","family":"De Almeida","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiujun","family":"Pi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M","family":"Hartmann-Scruggs","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Pumpens","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Center , Riga ,","place":["Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Holoshitz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,8,1]]},"reference":[{"key":"2025032411434004900_r1","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/art.1780330602","article-title":"How important are T cells in chronic rheumatoid synovitis?","volume":"33","author":"Firestein","year":"1990","journal-title":"Arthritis Rheum."},{"key":"2025032411434004900_r2","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/art.1780350702","article-title":"The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis","volume":"35","author":"Panayi","year":"1992","journal-title":"Arthritis Rheum."},{"key":"2025032411434004900_r3","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/art.1780301102","article-title":"The shared epitope hypothesis. 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Rheumatol."},{"key":"2025032411434004900_r6","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1084\/jem.181.5.1597","article-title":"Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases","volume":"181","author":"Wucherpfennig","year":"1995","journal-title":"J. Exp. Med."},{"key":"2025032411434004900_r7","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1172\/JCI119577","article-title":"Genetic bias in immune responses to a cassette shared by different microorganisms in patients with rheumatoid arthritis","volume":"100","author":"La Cava","year":"1997","journal-title":"J. Clin. 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