دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
المؤلفون: Li R; The Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Tang H; MS Research Unit, Biogen, Cambridge, MA, 02142, USA., Burns JC; MS Research Unit, Biogen, Cambridge, MA, 02142, USA.; Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02142, USA., Hopkins BT; Medicinal Chemistry, Biogen, Cambridge, MA, 02142, USA., Le Coz C; Division of Immunology and Allergy, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA., Zhang B; Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China., de Barcelos IP; Division of Human Genetics at Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Romberg N; Division of Immunology and Allergy, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Goldstein AC; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Division of Human Genetics at Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Banwell BL; Division of Neurology, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA., Luning Prak ET; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Mingueneau M; MS Research Unit, Biogen, Cambridge, MA, 02142, USA., Bar-Or A; The Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. amitbar@pennmedicine.upenn.edu.; Division of Neurology, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA. amitbar@pennmedicine.upenn.edu.
المصدر: Acta neuropathologica [Acta Neuropathol] 2022 Apr; Vol. 143 (4), pp. 505-521. Date of Electronic Publication: 2022 Mar 18.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0412041 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0533 (Electronic) Linking ISSN: 00016322 NLM ISO Abbreviation: Acta Neuropathol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Berlin : Springer Verlag
مواضيع طبية MeSH: Agammaglobulinaemia Tyrosine Kinase*/antagonists & inhibitors , B-Lymphocytes*/drug effects , B-Lymphocytes*/metabolism , Multiple Sclerosis*/drug therapy , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/therapeutic use, Cell Communication ; Humans
مستخلص: 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.
(© 2022. The Author(s).)
التعليقات: Comment in: Nat Rev Neurol. 2022 May;18(5):252. (PMID: 35379952)
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معلومات مُعتمدة: UM1 AI144288 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: Autoimmune diseases; B cells; Bruton’s tyrosine kinase (BTK); Co-stimulatory molecules; Cytokines; Immunometabolism
المشرفين على المادة: 0 (Protein Kinase Inhibitors)
EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
تواريخ الأحداث: Date Created: 20220318 Date Completed: 20220411 Latest Revision: 20230215
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8960592
DOI: 10.1007/s00401-022-02411-w
PMID: 35303161
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-0533
DOI:10.1007/s00401-022-02411-w