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- Title
BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
- Authors
Li, Rui; Tang, Hao; Burns, Jeremy C.; Hopkins, Brian T.; Le Coz, Carole; Zhang, Bo; de Barcelos, Isabella Peixoto; Romberg, Neil; Goldstein, Amy C.; Banwell, Brenda L.; Luning Prak, Eline T.; Mingueneau, Michael; Bar-Or, Amit
- 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.
- Subjects
BRUTON tyrosine kinase; B cells; MULTIPLE sclerosis; METABOLISM; METABOLIC regulation; T cells
- Publication
Acta Neuropathologica, 2022, Vol 143, Issue 4, p505
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-022-02411-w