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...
| Autori principali: | , , , , , , , , , , |
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| Natura: | Journal article |
| Lingua: | English |
| Pubblicazione: |
Wolters Kluwer
2019
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| _version_ | 1826299386211074048 |
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| author | Cargill, T Makuch, M Sadler, R Lighaam, L Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, E |
| author_facet | Cargill, T Makuch, M Sadler, R Lighaam, L Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, E |
| 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 (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 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 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1- Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4-responder index (r = 0.60, P = 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 | 2024-03-07T05:01:10Z |
| format | Journal article |
| id | oxford-uuid:d854631f-dd91-4bac-aefa-2d88eb6f6f84 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:01:10Z |
| publishDate | 2019 |
| publisher | Wolters Kluwer |
| record_format | dspace |
| spelling | oxford-uuid:d854631f-dd91-4bac-aefa-2d88eb6f6f842022-03-27T08:47:45ZActivated 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:d854631f-dd91-4bac-aefa-2d88eb6f6f84EnglishSymplectic Elements at OxfordWolters Kluwer2019Cargill, TMakuch, MSadler, RLighaam, LPeters, RVan Ham, MKlenerman, PBateman, ARispens, TBarnes, ECulver, E<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 (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 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 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1- Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4-responder index (r = 0.60, P = 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, L Peters, R Van Ham, M Klenerman, P Bateman, A Rispens, T Barnes, E Culver, E 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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