BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.

Abstract

Inhibition of Bruton's Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.

• Authors: Rui Li, Hao Tang, Jeremy C Burns, Brian T Hopkins, Carole Le Coz, Bo Zhang, Isabella Peixoto de Barcelos, Neil Romberg, Amy C Goldstein, Brenda L Banwell, Eline T Luning Prak, Michael Mingueneau, Amit Bar-Or
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 143 Issue 4 Pg. 505-521 (04 2022) ISSN: 1432-0533 [Electronic] Germany
• PMID: 35303161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Protein Kinase Inhibitors
• Agammaglobulinaemia Tyrosine Kinase

Topics

• Agammaglobulinaemia Tyrosine Kinase (antagonists & inhibitors)
• B-Lymphocytes (drug effects, metabolism)
• Cell Communication
• Humans
• Multiple Sclerosis (drug therapy)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)