{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:55:32Z","timestamp":1781110532893,"version":"3.54.1"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,9,16]]},"abstract":"<jats:p>\n                    Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT (\n                    <jats:italic>P<\/jats:italic>\n                    = 6.18 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    , OR = 3.73). Lys-71 showed the strongest association (\n                    <jats:italic>P<\/jats:italic>\n                    = 1.7 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    , OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT (\n                    <jats:italic>P<\/jats:italic>\n                    = 3.66 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). In mice, the I-E pocket amino acids Val-28, Phe-86, and Asn-88 were strongly associated with EAT. Structural modeling studies demonstrated that pocket P4 was critical for the development of HT, and pockets P1 and P4 influenced susceptibility to EAT. Surprisingly, the structures of the HT- and EAT-susceptible pockets were different. We conclude that specific MHC II pocket amino acid signatures determine susceptibility to HT and EAT by causing structural changes in peptide-binding pockets that may influence peptide binding, selectivity, and presentation. Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0806584105","type":"journal-article","created":{"date-parts":[[2008,9,8]],"date-time":"2008-09-08T20:55:04Z","timestamp":1220907304000},"page":"14034-14039","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice"],"prefix":"10.1073","volume":"105","author":[{"given":"Francesca","family":"Menconi","sequence":"first","affiliation":[{"name":"*Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Monti","sequence":"additional","affiliation":[{"name":"Division of Statistical Genetics, Columbia University, New York, NY 10032;"},{"name":"Department of Applied Health Sciences, University of Pavia, 27100 Pavia, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Division of Statistical Genetics, Columbia University, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiji","family":"Oashi","sequence":"additional","affiliation":[{"name":"Departments of \u00a7Structural and Chemical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Osman","sequence":"additional","affiliation":[{"name":"Departments of \u00a7Structural and Chemical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry F.","family":"Davies","sequence":"additional","affiliation":[{"name":"Medicine, Mount Sinai School of Medicine, New York, NY 10029;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Ban","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erlinda S.","family":"Concepcion","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheuk Wun","family":"Li","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaron","family":"Tomer","sequence":"additional","affiliation":[{"name":"*Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;"},{"name":"**Cincinnati VA Medical Center, Cincinnati, OH 45267"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,9,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.2.8182"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1997.4412"},{"key":"e_1_3_3_3_2","first-page":"721","volume-title":"Werner and Ingmar's the Thyroid","author":"Weetman AP","year":"2000","unstructured":"AP Weetman Werner and Ingmar's the Thyroid, eds LE Braverman, RD Utiger (Lippincott Williams and Wilkins, Philadelphia), pp. 721\u2013732 (2000)."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2002-0030"},{"key":"e_1_3_3_5_2","first-page":"107","article-title":"Infection, thyroid disease and autoimmunity","volume":"14","author":"Tomer Y","year":"1993","unstructured":"Y Tomer, TF Davies, Infection, thyroid disease and autoimmunity. 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