Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

Liza Rijvers, Jamie van Langelaar, Laurens Bogers, Marie José Melief, Steven C. Koetzier, Katelijn M. Blok, Annet F. Wierenga-Wolf, Helga E. de Vries, Jasper Rip, Odilia B.J. Corneth, Rudi W. Hendriks, Roland Grenningloh, Ursula Boschert, Joost Smolders, Marvin M. van Luijn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 relapsingremitting 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.

Original languageEnglish
Article numbere160909
JournalJCI insight
Volume7
Issue number16
DOIs
Publication statusPublished - 22 Aug 2022

Bibliographical note

Funding Information:
Support for this work was provided by the Dutch MS Research Foundation (19-1057 MS and 20-490f MS) and the healthcare business of Merck KGaA (CrossRef funder ID: 10.13039/100009945). We would like to acknowledge Harm de Wit and Peter van Geel for sorting the cells.

Publisher Copyright:
© 2022, Rijvers et al.

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