{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:32:32Z","timestamp":1762367552346,"version":"build-2065373602"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the relationship between Human Leukocyte Antigen-DR beta 1 (HLA-DRB1) shared epitope (SE) alleles and peripheral blood monocyte counts in disease-modifying antirheumatic drug-na\u00efve patients with rheumatoid arthritis (RA), and also the relationship between specific SE alleles and anti-cyclic citrullinated peptide antibody (anti-CCP Ab) titers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This retrospective single-center study included 86 Japanese patients with RA. HLA-DRB1 genotyping was performed, and SE alleles associated with a high risk of developing RA were classified into the S\n                      <jats:sub>2<\/jats:sub>\n                      (*04:01) and S\n                      <jats:sub>3P<\/jats:sub>\n                      (*01:01, *01:02, *04:04, *04:05, *04:08, and *10:01) categories. Patients were stratified based on monocyte count tertiles. The relationships between monocyte counts at diagnosis and clinical, serological, and genetic factors were analyzed. Logistic regression was used to identify independent factors associated with high monocyte counts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SE-positive patients, particularly those with S\n                      <jats:sub>3P<\/jats:sub>\n                      alleles, had significantly higher monocyte counts than SE-negative patients. A multivariate analysis revealed that male sex and S\n                      <jats:sub>3P<\/jats:sub>\n                      positivity, particularly HLA-DRB1 *01:01 or *04:05, were independently associated with higher monocyte counts. Patients carrying at least one S\n                      <jats:sub>3P<\/jats:sub>\n                      allele had significantly higher anti-CCP Ab titers, with patients homozygous for HLA-DRB1 *04:05 having the highest levels. A similar relationship was not found with HLA-DRB1 *01:01 despite its strong effect on monocyte counts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This is the first study to demonstrate a significant association between SE alleles and peripheral blood monocyte counts in RA. The results obtained suggest that specific SE alleles, particularly S\n                      <jats:sub>3P<\/jats:sub>\n                      alleles, contribute to the early pathogenesis of RA by enhancing monocyte-driven immune activation and anti-CCP Ab production.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0336214","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:30:02Z","timestamp":1762367402000},"page":"e0336214","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Relationship between HLA-DRB1 shared epitope alleles and peripheral blood monocyte counts in Japanese patients with rheumatoid arthritis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3645-3872","authenticated-orcid":true,"given":"Daisuke","family":"Hiraoka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6287-5011","authenticated-orcid":true,"given":"Jun","family":"Ishizaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Horie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Oryoji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin-ichi","family":"Mizuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuto","family":"Takenaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"issue":"10055","key":"pone.0336214.ref001","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"JS Smolen","year":"2016","journal-title":"Lancet"},{"issue":"23","key":"pone.0336214.ref002","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"IB McInnes","year":"2011","journal-title":"N Engl J Med"},{"issue":"11","key":"pone.0336214.ref003","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/art.1780301102","article-title":"The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis","volume":"30","author":"PK Gregersen","year":"1987","journal-title":"Arthritis Rheum"},{"issue":"9","key":"pone.0336214.ref004","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1074\/jbc.RA117.001013","article-title":"The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis","volume":"293","author":"YT Ting","year":"2018","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0336214.ref005","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1002\/art.20989","article-title":"New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility","volume":"52","author":"ST du Montcel","year":"2005","journal-title":"Arthritis Rheum"},{"issue":"3","key":"pone.0336214.ref006","doi-asserted-by":"crossref","DOI":"10.1186\/ar1949","article-title":"Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis","volume":"8","author":"L Michou","year":"2006","journal-title":"Arthritis Res Ther"},{"key":"pone.0336214.ref007","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.intimp.2018.10.016","article-title":"Monocytes in rheumatoid arthritis: circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis","volume":"65","author":"AK Rana","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"pone.0336214.ref008","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.3389\/fimmu.2019.02035","article-title":"Human monocyte subsets and phenotypes in major chronic inflammatory diseases","volume":"10","author":"TS Kapellos","year":"2019","journal-title":"Front Immunol"},{"issue":"12","key":"pone.0336214.ref009","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1007\/s10067-017-3815-2","article-title":"The association between the lymphocyte-monocyte ratio and disease activity in rheumatoid arthritis","volume":"36","author":"J Du","year":"2017","journal-title":"Clin Rheumatol"},{"issue":"2","key":"pone.0336214.ref010","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1136\/annrheumdis-2017-211649","article-title":"Monocyte alterations in rheumatoid arthritis are dominated by preterm release from bone marrow and prominent triggering in the joint","volume":"77","author":"B Smiljanovic","year":"2018","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"pone.0336214.ref011","doi-asserted-by":"crossref","DOI":"10.1002\/cti2.1237","article-title":"Rheumatoid arthritis CD14+ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease","volume":"10","author":"T McGarry","year":"2021","journal-title":"Clin Transl 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Weldon","year":"2015","journal-title":"J Rheumatol"},{"issue":"17","key":"pone.0336214.ref015","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2304199121","article-title":"The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis","volume":"121","author":"MA Thomas","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0336214.ref016","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1017\/thg.2017.3","article-title":"Heritability and GWAS studies for monocyte-lymphocyte ratio","volume":"20","author":"BD Lin","year":"2017","journal-title":"Twin Res Hum Genet"},{"issue":"6","key":"pone.0336214.ref017","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1002067","article-title":"Identification of nine novel loci associated with white blood cell subtypes in a Japanese population","volume":"7","author":"Y Okada","year":"2011","journal-title":"PLoS 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Rheumatol"},{"issue":"2","key":"pone.0336214.ref027","first-page":"219","article-title":"Differential association of HLA-DRB1 alleles in Japanese patients with early rheumatoid arthritis in relationship to autoantibodies to cyclic citrullinated peptide","volume":"25","author":"T Furuya","year":"2007","journal-title":"Clin Exp Rheumatol"},{"issue":"8","key":"pone.0336214.ref028","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1136\/ard.2009.118018","article-title":"HLA-DRB1*0901 lowers anti-cyclic citrullinated peptide antibody levels in Japanese patients with rheumatoid arthritis","volume":"69","author":"Y Okada","year":"2010","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"pone.0336214.ref029","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13075-016-1140-9","article-title":"Rheumatoid arthritis antigens homocitrulline and citrulline are generated by local myeloperoxidase and peptidyl arginine deiminases 2, 3 and 4 in rheumatoid nodule and synovial 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