{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:57Z","timestamp":1791312717885,"version":"4.3.1"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2018,9,1]],"date-time":"2018-09-01T00:00:00Z","timestamp":1535760000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases. While PBC is generally accepted to be an autoimmune disorder characterized by pathognomonic autoantibodies against mitochondrial antigens, the pathogenesis of PSC is less precisely defined; however, some degree of altered immunity toward autoantigens has been suggested. Follicular T helper (Tfh) cells, a distinct clusters of differentiation (CD)4 T\u2010cell subset specialized in facilitating antibody responses, have been shown to contribute to humoral autoimmunity in various disorders; yet, there is only limited information on possible alterations of Tfh cells in the context of cholestatic liver diseases. Thus, we addressed this important question by analyzing the frequency, activation status, and function of Tfh cells and frequencies of regulatory follicular T helper (Tfr) cells in well\u2010defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C\u2010X\u2010C motif) receptor 5 (CXCR5)+programmed death 1 (PD\u20101) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C\u2010C motif) receptor 7 (CCR7)lowCXCR5+PD\u20101+CD4+ Tfh cells was increased in both disorders compared to healthy donors, the increase was significantly more pronounced in PBC. Furthermore, in patients with PBC, Tfh cells displayed stronger expression of the activation markers OX40 and inducible costimulator of T cells, correlated with anti\u2010anti\u2010mitochondrial antibody M2 and immunoglobulin M titers, and were most significantly increased in patients with cirrhosis. Tfr cell numbers were similarly increased; however, Tfh\/Tfr ratios were unaltered in PSC and PBC. These alterations did not correlate with increased secretion of the Tfh signature cytokine interleukin\u201021 in sorted CD4 T cells. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Significant alterations occur in the Tfh cell compartment in cholestatic liver diseases, suggesting that Tfh cells influence the pathogenesis of PBC and to a lesser extend PSC.<\/jats:p>","DOI":"10.1002\/hep4.1226","type":"journal-article","created":{"date-parts":[[2018,9,7]],"date-time":"2018-09-07T15:27:36Z","timestamp":1536334056000},"page":"1051-1063","source":"Crossref","is-referenced-by-count":21,"title":["Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"2","author":[{"given":"Leonie","family":"Adam","sequence":"first","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Zoldan","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schultheiss","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-8729","authenticated-orcid":false,"given":"Dominik","family":"Bettinger","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"},{"name":"Berta\u2010Ottenstein Program, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Neumann\u2010Haefelin","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Thimme","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Boettler","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Cewnter, Faculty of Medicine,University of Freiburg,Freiburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,9,7]]},"reference":[{"key":"hep41226-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/S0140-6736(15)00154-3","article-title":"Primary biliary cirrhosis","volume":"386","year":"2015","journal-title":"Lancet"},{"key":"hep41226-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJMra1506330","article-title":"Primary sclerosing cholangitis","volume":"375","year":"2016","journal-title":"N Engl J Med"},{"key":"hep41226-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mam.2013.10.001","article-title":"Chronic cholestatic liver diseases: clues from histopathology for pathogenesis","volume":"37","year":"2014","journal-title":"Mol Aspects Med"},{"key":"hep41226-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1034\/j.1600-0528.2002.017402.x","article-title":"Primary biliary cirrhosis: an orchestrated immune response against epithelial cells","volume":"174","year":"2000","journal-title":"Immunol Rev"},{"key":"hep41226-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev-immunol-041015-055605","article-title":"Follicular helper T cells","volume":"34","year":"2016","journal-title":"Annu Rev Immunol"},{"key":"hep41226-bib-0006-20240114","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.immuni.2013.08.031","article-title":"International AIDS Vaccine Initiative Protocol C Principal Investigators. 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