دورية أكاديمية
BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
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) |
References: | Blood. 2012 Apr 19;119(16):3744-56. (PMID: 22383797) J Immunol. 2001 Nov 15;167(10):5669-77. (PMID: 11698439) Nat Immunol. 2020 Mar;21(3):331-342. (PMID: 32066950) Nat Immunol. 2017 Mar;18(3):303-312. (PMID: 28114292) Immunity. 2003 Nov;19(5):669-78. (PMID: 14614854) Brain. 2021 Jun 22;144(5):1396-1408. (PMID: 33724342) Immunology. 2012 Aug;136(4):370-9. (PMID: 22444240) Nat Immunol. 2018 Jul;19(7):696-707. (PMID: 29925992) Clin Immunol. 2016 Dec;173:124-132. (PMID: 27717695) Brain Plast. 2020 Oct 01;5(2):123-133. (PMID: 33282676) Arthritis Rheumatol. 2017 Jun;69(6):1313-1324. (PMID: 28141917) Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13152-7. (PMID: 9371815) Sci Transl Med. 2019 Nov 13;11(518):. (PMID: 31723036) Clin Transl Immunology. 2021 Jun 14;10(6):e1295. (PMID: 34141433) Science. 2019 Jan 11;363(6423):. (PMID: 30630899) Ann Neurol. 2018 Feb;83(2):223-234. (PMID: 29328531) Nat Rev Immunol. 2018 Jan;18(1):19-34. (PMID: 28944771) J Immunol. 2019 May 15;202(10):2888-2906. (PMID: 30988116) Cell. 2019 Apr 4;177(2):492-493. (PMID: 30951673) Ann Neurol. 2010 Apr;67(4):452-61. (PMID: 20437580) Ann Neurol. 2020 Jul;88(1):81-92. (PMID: 32286701) Ann Neurol. 2010 Oct;68(4):477-93. (PMID: 20976767) Nat Immunol. 2003 Mar;4(3):280-6. (PMID: 12563258) Nat Rev Drug Discov. 2021 Mar;20(3):179-199. (PMID: 33324003) PLoS One. 2017 Jul 24;12(7):e0181782. (PMID: 28742141) Acta Neuropathol. 2017 Jan;133(1):25-42. (PMID: 27796537) Front Immunol. 2020 Nov 06;11:588021. (PMID: 33240276) Brain. 2021 Sep 4;144(8):2361-2374. (PMID: 34145876) Nat Immunol. 2016 Oct;17(10):1197-1205. (PMID: 27573866) Front Immunol. 2018 Jun 07;9:888. (PMID: 29930549) J Biol Chem. 2001 May 11;276(19):16201-6. (PMID: 11279148) Acta Neuropathol. 2021 Jun;141(6):881-899. (PMID: 33779783) Acta Neuropathol. 2020 Oct;140(4):535-548. (PMID: 32761407) J Clin Invest. 1997 Jun 1;99(11):2664-71. (PMID: 9169496) JCI Insight. 2017 Apr 6;2(7):e90111. (PMID: 28405610) Nature. 2021 Sep;597(7878):709-714. (PMID: 34497421) Brain. 2021 Jul 28;144(6):1646-1654. (PMID: 33876200) J Exp Med. 2013 Dec 16;210(13):2921-37. (PMID: 24323356) Brain. 2019 Sep 1;142(9):2787-2799. (PMID: 31497864) Cell. 2018 Sep 20;175(1):85-100.e23. (PMID: 30173916) Ann Neurol. 2018 Apr;83(4):739-755. (PMID: 29518260) J Biol Chem. 1999 Oct 22;274(43):30644-50. (PMID: 10521450) Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):359-64. (PMID: 11756681) J Immunol. 2016 Jul 1;197(1):58-67. (PMID: 27226091) Eur J Immunol. 1994 Dec;24(12):3100-5. (PMID: 7805739) Front Immunol. 2020 Mar 20;11:374. (PMID: 32265902) Front Immunol. 2017 Nov 08;8:1454. (PMID: 29167667) Sci Rep. 2019 Jul 30;9(1):11069. (PMID: 31363127) Lancet Neurol. 2021 Jun;20(6):470-483. (PMID: 33930317) Sci Immunol. 2020 Nov 20;5(53):. (PMID: 33219152) Lancet Neurol. 2021 Sep;20(9):729-738. (PMID: 34418400) Brain. 2016 Mar;139(Pt 3):807-15. (PMID: 26912645) J Neuroimmunol. 2017 Aug 15;309:88-99. (PMID: 28601295) Nat Rev Cancer. 2014 Apr;14(4):219-32. (PMID: 24658273) N Engl J Med. 2019 Jun 20;380(25):2406-2417. (PMID: 31075187) J Immunol. 2017 Apr 15;198(8):3245-3254. (PMID: 28275140) JAMA Neurol. 2019 Dec 1;76(12):1474-1483. (PMID: 31403674) |
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 |
تدمد: | 1432-0533 |
---|---|
DOI: | 10.1007/s00401-022-02411-w |