biostudies-literatureLi RBiogenthe Melissa and Paul Anderson Gift Fund at the University of PennsylvaniaNIAID NIH HHSCenter for Mitochondrial and Epigenomic Medicine505-521https://www.ebi.ac.uk/biostudies/studies/S-EPMC8960592biostudies-literatureUnknown143(4)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 exaActa neuropathologicaBTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.PMC8960592UM1 AI144288Romberg NBurns JCHopkins BTLe Coz CGoldstein ACLi RBanwell BLBar-Or ATang HMingueneau MLuning Prak ETZhang Bde Barcelos IPfalseBTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.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 exa2022-01-01T00:00:00Z2022 Apr2026-05-31T03:14:45.752Z2024-11-05T18:22:23.173ZS-EPMC89605923530316110.1007/s00401-022-02411-w