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  • Title: Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib.
    Author: Rijvers L, van Langelaar J, Bogers L, Melief MJ, Koetzier SC, Blok KM, Wierenga-Wolf AF, de Vries HE, Rip J, Corneth OB, Hendriks RW, Grenningloh R, Boschert U, Smolders J, van Luijn MM.
    Journal: JCI Insight; 2022 Aug 22; 7(16):. PubMed ID: 35852869.
    Abstract:
    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.
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