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

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.

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

“…59 BTK inhibition by Evobrutinib impaired the ability of CXCR3+B cells to penetrate through human brain endothelial layers. 60 The Immune-Related Mechanisms of BTK Inhibition in the Central Nervous System Targeting B Cell As mentioned above, BTK is a vital component of BCR signaling regulating B-cell functions. Targeting BTK has been widely studied and applied in the treatment of multiple sclerosis (MS).…”

“…Evobrutinib also prevented memory B cell migration across the brain endothelial layer and maturation into ASCs, which can be considered a promising therapeutic approach to attenuate local antibody production in MS patients. 60 A recent study shed new light on the regulatory function of BTKi on B cells in MS. Li et al 69 reported that the treatment of BTKi could inhibit mitochondrial respiration in human B cells in vitro, resulting in an anti-inflammatory shift in B cell properties. The expression of costimulatory molecules is reduced in B cells, limiting their function as antigen-presenting cells to activate pathogenic T cells.…”

“… 59 BTK inhibition by Evobrutinib impaired the ability of CXCR3+B cells to penetrate through human brain endothelial layers. 60 …”

“…Furthermore, using B-cell depletion and BTK inhibition in sequence is likely to be an effective approach to achieve rapid control of MS symptoms and avoid long-term compromising humoral immunity. 61 , 62 , 68 Although the increased expression level of BTK was observed in MS patients, 60 , 69 the exact mechanisms in which BTK involves in the development of MS remain to be further illustrated. Therefore, several studies have emerged in an attempt to address this question.…”

“…Evobrutinib also prevented memory B cell migration across the brain endothelial layer and maturation into ASCs, which can be considered a promising therapeutic approach to attenuate local antibody production in MS patients. 60 …”