Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis
<p><strong>Objectives: </strong>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 differentiat...
| Hlavní autoři: | , , , , , , , , , , |
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| Médium: | Journal article |
| Jazyk: | English |
| Vydáno: |
Wolters Kluwer Health
2019
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| _version_ | 1826305869138100224 |
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| author | Cargill, T Makuch, M Sadler, R Lighaam, LC Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, EL |
| author_facet | Cargill, T Makuch, M Sadler, R Lighaam, LC Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, EL |
| author_sort | Cargill, T |
| collection | OXFORD |
| description | <p><strong>Objectives: </strong>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.</p> <p><strong>Methods: </strong>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–responder index and clinical parameters.</p> <p><strong>Results: </strong>Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (<em>P</em> < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, <em>P</em>= 0.003; Tfh2, <em>P</em> = 0.0006; Th17, <em>P</em> = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (<em>P</em> = 0.01) correlated with the PD-1+ Tfh2 subset (<em>r</em> = 0.69, <em>P</em> = 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 (<em>r</em> = 0.89, <em>P</em> = 0.02) and PD-1+ Tfh17 (<em>r</em> = 0.83, <em>P</em> = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1− Tfh (<em>P</em> = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (<em>r</em> = 0.70, <em>P</em> = 0.002), sIgE (<em>r</em> = 0.66, <em>P</em> = 0.006), and IgG4–responder index (<em>r</em> = 0.60, <em>P</em> = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues.</p> <p><strong>Conclusions: </strong>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.</p> |
| first_indexed | 2024-03-07T06:39:23Z |
| format | Journal article |
| id | oxford-uuid:f8bdbfa5-397d-42a4-8bba-09dba20a3a80 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:39:23Z |
| publishDate | 2019 |
| publisher | Wolters Kluwer Health |
| record_format | dspace |
| spelling | oxford-uuid:f8bdbfa5-397d-42a4-8bba-09dba20a3a802022-03-27T12:52:48ZActivated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f8bdbfa5-397d-42a4-8bba-09dba20a3a80EnglishSymplectic Elements at OxfordWolters Kluwer Health2019Cargill, TMakuch, MSadler, RLighaam, LCPeters, RVan Ham, MKlenerman, PBateman, ARispens, TBarnes, ECulver, EL<p><strong>Objectives: </strong>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.</p> <p><strong>Methods: </strong>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–responder index and clinical parameters.</p> <p><strong>Results: </strong>Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (<em>P</em> < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, <em>P</em>= 0.003; Tfh2, <em>P</em> = 0.0006; Th17, <em>P</em> = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (<em>P</em> = 0.01) correlated with the PD-1+ Tfh2 subset (<em>r</em> = 0.69, <em>P</em> = 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 (<em>r</em> = 0.89, <em>P</em> = 0.02) and PD-1+ Tfh17 (<em>r</em> = 0.83, <em>P</em> = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1− Tfh (<em>P</em> = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (<em>r</em> = 0.70, <em>P</em> = 0.002), sIgE (<em>r</em> = 0.66, <em>P</em> = 0.006), and IgG4–responder index (<em>r</em> = 0.60, <em>P</em> = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues.</p> <p><strong>Conclusions: </strong>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.</p> |
| spellingShingle | Cargill, T Makuch, M Sadler, R Lighaam, LC Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, EL Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title | Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title_full | Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title_fullStr | Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title_full_unstemmed | Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title_short | Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis |
| title_sort | activated t follicular helper 2 cells are associated with disease activity in igg4 related sclerosing cholangitis and pancreatitis |
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