{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:03:13Z","timestamp":1790960593050,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["FO354\/14\u20101"],"award-info":[{"award-number":["FO354\/14\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["INSAID"],"award-info":[{"award-number":["INSAID"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cells or serum samples were obtained from healthy controls (n\u00a0=\u00a072) and systemic JIA patients (n\u00a0=\u00a0171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)\u2014polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self\u2010antigen arrays and enzyme\u2010linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Differentiation of systemic JIA\u2013naive T helper cells toward Th1 cells resulted in low expression levels of interferon\u2010\u03b3 (IFN\u03b3) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin\u201021 (IL\u201021), which negatively correlated with cellular expression of IFN\u03b3 and eomesodermin. In both in vitro and ex vivo analyses, IL\u201021 together with programmed cell death 1 (PD\u20101), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh\/Tph cell phenotype. Retrospective analysis of whole\u2010blood RNA\u2010sequencing data demonstrated that Bcl\u20106, a master transcription factor in Tfh\/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self\u2010antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh\/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42409-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42409","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T12:24:44Z","timestamp":1669033484000},"page":"826-841","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Aberrant Naive\n                    <scp>CD4<\/scp>\n                    \u2013Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help"],"prefix":"10.1002","volume":"75","author":[{"given":"Julia","family":"Kuehn","sequence":"first","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's Hospital  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Schleifenbaum","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's Hospital  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Hendling","sequence":"additional","affiliation":[{"name":"Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Siebenhandl","sequence":"additional","affiliation":[{"name":"Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Krainer","sequence":"additional","affiliation":[{"name":"Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Fuehner","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's Hospital  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Hellige","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's Hospital  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Park","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's Hospital  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9247-4729","authenticated-orcid":false,"given":"Claas","family":"Hinze","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology and Immunology University Children's 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