Article
Distinct effects of five JAK inhibitors in the modulation of human B cell activation
Search Medline for
Authors
-
Natalie Frede
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Janika Hueppe
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Raquel Lorenzetti
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Arianna Troilo
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Marei-Theresa Schleyer
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Reinhard Voll
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Jens Thiel
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Nils Venhoff
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
-
Marta Rizzi
- Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
| Published: | September 9, 2020 |
|---|
Outline
Text
Introduction: JAK inhibitors have been successfully introduced in the treatment of rheumatoid arthritis and are in clinical trials for numerous other autoimmune diseases. There are four different Janus kinases (JAKs), and the available drugs target each of them with different affinity. The outcome of immunomodulation through JAK inhibitors will hence largely depend on the intrinsic expression of JAKs, the cytokine environment and targeted cell type. Comparative studies investigating the effect of different JAK inhibitors on T cells and monocytes are available, but detailed studies on B cells are missing.
Methods: B cell subpopulations of RA patients treated with baricitinib/tofacitinib were assessed by flow cytometry. For in vitro studies, healthy donor B cells were stimulated with CpG, treated with scalar doses of the JAK inhibitors tofacitinib, baricitinib, ruxolitinib, upadacitinib or filgotinib and analysed by flow cytometry. Cytokine secretion was measured by Cytokine Multiplex Assay.
Results: B cell phenotyping of RA patients treated with baricitinib or tofacitinib showed an increase in marginal zone (MZ) B cells. To investigate this further, we turned to an in vitro model of T-cell-independent B cell activation and observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. When assessing B cell-subpopulations, we detected an altered B cell differentiation with a significant increase in MZ-like B cells, which led to a subsequent increase in plasmablast differentiation in the first days of culture, most pronounced with pan-JAK inhibitor tofacitinib. Notably, we further observed a >50% reduction of switched memory formation, especially with JAK1/2 inhibition.
We next assessed the role of autocrine cytokine signalling and found that JAK inhibition modulated cytokine secretion towards pro-inflammatory cytokines, with reduced IL10, but increased IL6 and TNF secretion. JAK inhibition further reduced induction of STAT3 expression as well as STAT3 phosphorylation, which plays an important role in proliferation, class switching, and differentiation of human B cells.
Conclusion: In conclusion, JAK inhibition has a major effect on B cell activation and maturation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.
Disclosures: Nothing to disclose
