Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis
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 precis...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2018-09-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1226 |
| _version_ | 1811173872361275392 |
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| author | Leonie Adam Katharina Zoldan Maike Hofmann Michael Schultheiss Dominik Bettinger Christoph Neumann‐Haefelin Robert Thimme Tobias Boettler |
| author_facet | Leonie Adam Katharina Zoldan Maike Hofmann Michael Schultheiss Dominik Bettinger Christoph Neumann‐Haefelin Robert Thimme Tobias Boettler |
| author_sort | Leonie Adam |
| collection | DOAJ |
| description | 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‐cell 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‐defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C‐X‐C motif) receptor 5 (CXCR5)+programmed death 1 (PD‐1) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C‐C motif) receptor 7 (CCR7)lowCXCR5+PD‐1+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‐anti‐mitochondrial 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‐21 in sorted CD4 T cells. Conclusion: 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. |
| first_indexed | 2024-04-10T17:54:02Z |
| format | Article |
| id | doaj.art-7058578fd8124fcc8bd9f40941d3bcaf |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T17:54:02Z |
| publishDate | 2018-09-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-7058578fd8124fcc8bd9f40941d3bcaf2023-02-02T19:12:39ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2018-09-01291051106310.1002/hep4.1226Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing CholangitisLeonie Adam0Katharina Zoldan1Maike Hofmann2Michael Schultheiss3Dominik Bettinger4Christoph Neumann‐Haefelin5Robert Thimme6Tobias Boettler7Department of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyDepartment of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg GermanyPrimary 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‐cell 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‐defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C‐X‐C motif) receptor 5 (CXCR5)+programmed death 1 (PD‐1) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C‐C motif) receptor 7 (CCR7)lowCXCR5+PD‐1+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‐anti‐mitochondrial 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‐21 in sorted CD4 T cells. Conclusion: 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.https://doi.org/10.1002/hep4.1226 |
| spellingShingle | Leonie Adam Katharina Zoldan Maike Hofmann Michael Schultheiss Dominik Bettinger Christoph Neumann‐Haefelin Robert Thimme Tobias Boettler Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Hepatology Communications |
| title | Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis |
| title_full | Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis |
| title_fullStr | Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis |
| title_full_unstemmed | Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis |
| title_short | Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis |
| title_sort | follicular t helper cell signatures in primary biliary cholangitis and primary sclerosing cholangitis |
| url | https://doi.org/10.1002/hep4.1226 |
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