JAK inhibitors differentially modulate B cell activation, maturation and function : A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients with rheumatoid arthritis
Copyright © 2023 Frede, Lorenzetti, Hüppe, Janowska, Troilo, Schleyer, Venhoff, Voll, Thiel, Venhoff and Rizzi..
Background: Janus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment.
Methods: To this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways.
Results: While B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells.
Conclusion: JAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Frontiers in immunology - 14(2023) vom: 07., Seite 1087986 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Frede, Natalie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.02.2023 Date Revised 07.03.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.3389/fimmu.2023.1087986 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM352862181 |
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| 100 | 1 | |a Frede, Natalie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a JAK inhibitors differentially modulate B cell activation, maturation and function |b A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients with rheumatoid arthritis |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 14.02.2023 | ||
| 500 | |a Date Revised 07.03.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Frede, Lorenzetti, Hüppe, Janowska, Troilo, Schleyer, Venhoff, Voll, Thiel, Venhoff and Rizzi. | ||
| 520 | |a Background: Janus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment | ||
| 520 | |a Methods: To this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways | ||
| 520 | |a Results: While B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells | ||
| 520 | |a Conclusion: JAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a B cells | |
| 650 | 4 | |a JAK inhibition | |
| 650 | 4 | |a baricitinib | |
| 650 | 4 | |a filgotinib | |
| 650 | 4 | |a rheumatoid arthritis | |
| 650 | 4 | |a ruxolitinib | |
| 650 | 4 | |a tofacitinib | |
| 650 | 4 | |a upadacitinib | |
| 650 | 7 | |a Janus Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Immunomodulating Agents |2 NLM | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 700 | 1 | |a Lorenzetti, Raquel |e verfasserin |4 aut | |
| 700 | 1 | |a Hüppe, Janika M |e verfasserin |4 aut | |
| 700 | 1 | |a Janowska, Iga |e verfasserin |4 aut | |
| 700 | 1 | |a Troilo, Arianna |e verfasserin |4 aut | |
| 700 | 1 | |a Schleyer, Marei-Theresa |e verfasserin |4 aut | |
| 700 | 1 | |a Venhoff, Ana C |e verfasserin |4 aut | |
| 700 | 1 | |a Voll, Reinhard E |e verfasserin |4 aut | |
| 700 | 1 | |a Thiel, Jens |e verfasserin |4 aut | |
| 700 | 1 | |a Venhoff, Nils |e verfasserin |4 aut | |
| 700 | 1 | |a Rizzi, Marta |e verfasserin |4 aut | |
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