{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:46:34Z","timestamp":1786545994978,"version":"build-2736575974"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"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":["Clin Transl Gastroenterol","Clinical and Translational Gastroenterology"],"abstract":"\n OBJECTIVES:<\/jats:title>\n Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC\/AIP.<\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n Circulating Tfh-cell subsets were characterized by multiparametric flow cytometry in IgG4-SC\/AIP (n = 18), disease controls with primary sclerosing cholangitis (n = 8), and healthy controls (HCs, n = 9). Tissue Tfh cells were characterized in IgG4-SC\/AIP (n = 12) and disease control (n = 10) specimens. Activated PD1+ Tfh cells were cocultured with CD27+ memory B cells to assess their capacity to support B-cell differentiation. Disease activity was assessed using the IgG4\u2013responder index and clinical parameters.<\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC\/AIP, primary sclerosing cholangitis, and HC (\n P<\/jats:italic>\n < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1,\n P<\/jats:italic>\n = 0.003; Tfh2,\n P<\/jats:italic>\n = 0.0006; Th17,\n P<\/jats:italic>\n = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (\n P<\/jats:italic>\n = 0.01) correlated with the PD-1+ Tfh2 subset (\n r<\/jats:italic>\n = 0.69,\n P<\/jats:italic>\n = 0.03). Increased IL-4 and IL-21 cytokine production from stimulated cells of IgG4-SC\/AIP, important in IgG4 class switch and proliferation, correlated with PD-1+ Tfh2 (\n r<\/jats:italic>\n = 0.89,\n P<\/jats:italic>\n = 0.02) and PD-1+ Tfh17 (\n r<\/jats:italic>\n = 0.83,\n P<\/jats:italic>\n = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1\u2212 Tfh (\n P<\/jats:italic>\n = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (\n r<\/jats:italic>\n = 0.70,\n P<\/jats:italic>\n = 0.002), sIgE (\n r<\/jats:italic>\n = 0.66,\n P<\/jats:italic>\n = 0.006), and IgG4\u2013responder index (\n r<\/jats:italic>\n = 0.60,\n P<\/jats:italic>\n = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC\/AIP tissues.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n Circulating and tissue-activated Tfh cells are expanded in IgG4-SC\/AIP, correlate with disease activity, and can drive class switch and proliferation of IgG4-committed B cells. PD1+ Tfh2 cells may be a biomarker of active disease and a potential target for immunotherapy.<\/jats:p>\n <\/jats:sec>","DOI":"10.14309\/ctg.0000000000000020","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T03:50:40Z","timestamp":1556509840000},"page":"e00020","source":"Crossref","is-referenced-by-count":39,"title":["Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis"],"prefix":"10.14309","volume":"10","author":[{"given":"Tamsin","family":"Cargill","sequence":"first","affiliation":[{"name":"Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, UK;"},{"name":"Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Makuch","sequence":"additional","affiliation":[{"name":"Sanquin, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Sadler","sequence":"additional","affiliation":[{"name":"Department of Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C.","family":"Lighaam","sequence":"additional","affiliation":[{"name":"Sanquin, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Peters","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, UK;"},{"name":"Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"van Ham","sequence":"additional","affiliation":[{"name":"Sanquin, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Klenerman","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, UK;"},{"name":"Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Bateman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Rispens","sequence":"additional","affiliation":[{"name":"Sanquin, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Barnes","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, UK;"},{"name":"Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Culver","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, UK;"},{"name":"Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,4,26]]},"reference":[{"key":"R1-20230814","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/nrgastro.2016.132","article-title":"IgG4-related hepatobiliary disease: An overview","volume":"13","author":"Culver","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"R2-20230814","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1038\/ajg.2014.223","article-title":"Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort","volume":"109","author":"Huggett","year":"2014","journal-title":"Am J Gastroenterol"},{"key":"R3-20230814","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1016\/j.cgh.2017.02.007","article-title":"Increases in IgE, eosinophils, and mast cells can be used in diagnosis 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