Human T-bet<sup>+</sup> 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

doi:10.1172/jci.insight.160909

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

Liza Rijvers,¹ Jamie van Langelaar,¹ Laurens Bogers,¹ Marie-José Melief,¹ Steven C. Koetzier,¹ Katelijn M. Blok,² Annet F. Wierenga-Wolf,¹ Helga E. De Vries,³ Jasper Rip,¹ Odilia B.J. Corneth,⁴ Rudi W. Hendriks,⁴ Roland Grenningloh,⁵ Ursula Boschert,⁶ Joost Smolders,¹ and Marvin M. van Luijn¹

Published July 19, 2022 - More info

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Abstract

Recent clinical trials show 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. In contrast to BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells of relapsing and secondary progressive MS patients versus 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 of clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro T_FH-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli IFN-γ and CpG-ODN, whilst the expression of T-bet and T-bet-associated molecules CXCR3, CD21 and CD11c were 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 in MS patients.

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

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

Liza Rijvers,1 Jamie van Langelaar,1 Laurens Bogers,1 Marie-José Melief,1 Steven C. Koetzier,1 Katelijn M. Blok,2 Annet F. Wierenga-Wolf,1 Helga E. De Vries,3 Jasper Rip,1 Odilia B.J. Corneth,4 Rudi W. Hendriks,4 Roland Grenningloh,5 Ursula Boschert,6 Joost Smolders,1 and Marvin M. van Luijn1

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