期刊
ACTA NEUROPATHOLOGICA
卷 143, 期 4, 页码 505-521出版社
SPRINGER
DOI: 10.1007/s00401-022-02411-w
关键词
Bruton's tyrosine kinase (BTK); B cells; Immunometabolism; Autoimmune diseases; Co-stimulatory molecules; Cytokines
资金
- Melissa and Paul Anderson Gift Fund at the University of Pennsylvania
- Center for Mitochondrial and Epigenomic Medicine (CMEM) award
- University of Pennsylvania
- Biogen, MA
Inhibition of Bruton's Tyrosine Kinase (BTKi) is a promising therapy for autoimmune diseases. This study demonstrates that BTKi attenuates B-cell:T-cell interactions by modulating B-cell metabolic pathways and mediates an anti-inflammatory modulation of B cells. The study suggests that targeting B-cell metabolism may be a viable therapeutic approach for pro-inflammatory B cells.
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.
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