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Frede, N; Lorenzetti, R; Hüppe, JM; Janowska, I; Troilo, A; Schleyer, MT; Venhoff, AC; Voll, RE; Thiel, J; Venhoff, N; Rizzi, M.
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.
Front Immunol. 2023; 14:1087986 Doi: 10.3389/fimmu.2023.1087986 [OPEN ACCESS]
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Co-authors Med Uni Graz: Thiel Jens
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Abstract:: 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.
Find related publications in this database (using NLM MeSH Indexing): Humans - administration & dosage; Janus Kinase Inhibitors - pharmacology, therapeutic use; Immunomodulating Agents - administration & dosage; Arthritis, Rheumatoid - drug therapy; Anti-Inflammatory Agents - pharmacology; Cell Differentiation - administration & dosage
Find related publications in this database (Keywords): JAK inhibition; B cells; rheumatoid arthritis; tofacitinib; baricitinib; ruxolitinib; upadacitinib; filgotinib