JAK inhibitors (baricitinib, tofacitinib, upadacitinib), except for filgotinib, significantly reduce plasmablast differentiation but only partly inhibit activation of naïve B cells and exert a more modest effect on TNF and IL-8 production. Unlike other JAK inhibitors, filgotinib selectively inhibits STAT5 phosphorylation without affecting STAT3 phosphorylation in response to IL-21.
ABSTRACT
B cells play a crucial role in autoimmune diseases, as evidenced by autoantibody responses and the effectiveness of B cell-targeted therapies. Janus kinase inhibitors (JAKi), which target downstream signaling of cytokine receptors, are potent rheumatic disease-modifying drugs. However, besides reducing inflammation, JAKi may impact the adaptive immune system. In this study, we examined the effects of JAKi on B-cell function using in vitro cultures and multiparameter flow cytometry. The results show a JAKi-mediated reduction in plasma cell differentiation, primarily by inhibition of memory B-cell stimulation and proliferation. JAKi exposure resulted in stalling R848, IL-2, and IL-21 stimulated B cells in an intermediate activated state with elevated naïve cells displaying increased expression of CXCR5, CD71, CD22, and CD20. In addition, the data demonstrate a moderate JAKi-mediated reduction of B cell TNF and IL-8 cytokine expression following stimulation. Importantly, the efficacy varied greatly between drugs; tofacitinib and upadacitinib (pan JAKi; JAK1i) exhibited the strongest impact, while baricitinib (JAK1/JAK2i) showed donor-dependent variation, and filgotinib (JAK1i) had no effect. All JAKi, except filgotinib, inhibited IL-2 or IL-21-induced STAT3 phosphorylation. Still, filgotinib demonstrated similar inhibition of phospho-STAT5 as other JAKi following IL-21. These findings underscore the therapeutic impact of JAKi through the modulation of B-cell functions.