JCI Insight (Aug 2022)

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

Journal volume & issue
Vol. 7, no. 16

Abstract

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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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