BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
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DOI：
10.1007/s00401-022-02411-w
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发表时间：
2022-04
影响因子：
12.7
通讯作者：
Bar-Or A
中科院分区：
文献类型：
--
作者：
Li R;Tang H;Burns JC;Hopkins BT;Le Coz C;Zhang B;de Barcelos IP;Romberg N;Goldstein AC;Banwell BL;Luning Prak ET;Mingueneau M;Bar-Or A
抑制布鲁顿酪氨酸激酶（BTKi）现在被视为治疗包括多发性硬化（MS）在内的自身免疫性疾病的有希望的下一代B细胞靶向疗法。然而，令人惊讶的是，关于BTKi如何影响B细胞的MS疾病相关功能，我们知之甚少。在这里，我们证明，除了其预期的影响B细胞活化，BTKi减弱B细胞：T细胞的相互作用，通过一种新的机制，涉及调制的B细胞代谢途径，这反过来又介导了抗炎调制的B细胞。在体外，BTKi以及B细胞线粒体呼吸的直接抑制（但不是糖酵解）限制了B细胞充当T细胞的APC的能力。当检查线粒体呼吸链突变的罕见患者的B细胞时，代谢在调节人类B细胞反应中的作用得到证实。我们进一步证明BTKi和离体代谢调节可以消除未治疗的MS患者的B细胞的异常活化和共刺激分子表达。最后，作为健康志愿者的1期研究中的原理证明，我们证实体内BTKi治疗减少循环B细胞线粒体呼吸，减少其激活诱导的共刺激分子表达，并介导与T细胞促炎反应减弱相关的B细胞反应的抗炎转变。这些数据共同阐明了一种新的非消耗机制，BTKi通过该机制介导其对疾病相关B细胞应答的影响，并揭示了调节B细胞代谢可能是靶向促炎性B细胞的可行治疗方法。在线版本包含补充材料，可通过10.1007/s 00401 -022-02411-w获得。
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. The online version contains supplementary material available at 10.1007/s00401-022-02411-w.
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