TY - JOUR AU - Rijvers, Liza AU - van Langelaar, Jamie AU - Bogers, Laurens AU - Melief, Marie-José AU - Koetzier, Steven C. AU - Blok, Katelijn M. AU - Wierenga-Wolf, Annet F. AU - de Vries, Helga E. AU - Rip, Jasper AU - Corneth, Odilia B.J. AU - Hendriks, Rudi W. AU - Grenningloh, Roland AU - Boschert, Ursula AU - Smolders, Joost AU - van Luijn, Marvin M. T1 - Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib PY - 2022/08/22/ AB - Recent clinical trials have shown promising results for the next-generation Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti–VLA-4 antibody) treatment. Under in vitro T follicular helper–like conditions, BTK phosphorylation was enhanced by T-bet–inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet–associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.160909 VL - 7 IS - 16 UR - https://doi.org/10.1172/jci.insight.160909 PB - The American Society for Clinical Investigation ER -