Naouar, Ikbel, Pangan, Andrei, Zuo, Michelle, Champagne-Jorgens, Kevin, Patel, Jyot, Wang, Angela, Pu, Annie, Ward, Lesley, Ahn, Jennifer, Cenni, Bruno, Nuesslein-Hildesheim, Barbara, Probstel, Anne-Katrin, Gommerman, Jennifer and Ramaglia, Valeria (2026) Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury. Nature immunology, 27 (1). pp. 48-60. ISSN 1529-2916

Abstract

In multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the brain leptomeninges associate with cortical gray matter injury. Using a model of Th17 cell-driven experimental autoimmune encephalomyelitis in mice, we found that inhibitors of Bruton's tyrosine kinase (BTKi) prevented TLT formation and cortical pathology in a B cell activating factor (BAFF)-dependent manner. BTKi reduced expression of lymphotoxin ligands, and cotreatment with a lymphotoxin-β receptor agonist abrogated the benefits of BTKi. TLT and cortical pathology tracked with a high CXCL13:BAFF ratio in the leptomeninges, which was reduced by BTKi. Moreover, we observed high CXCL13:BAFF ratios in post mortem cerebral spinal fluid from patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic rim lesions. In summary, using experimental autoimmune encephalomyelitis, we revealed a molecular circuit that leads to TLT formation and cortical injury with translational relevance for detection of this pathology in patients with MS.

Item Type:	Article
Keywords:	Animals Chemokine CXCL13 Gray Matter Humans Mice Encephalomyelitis, Autoimmune, Experimental Meninges B-Cell Activating Factor Multiple Sclerosis Female Male Mice, Inbred C57BL Lymphotoxin-alpha Th17 Cells Tertiary Lymphoid Structures B-Lymphocytes
Date Deposited:	17 Jan 2026 00:46
Last Modified:	17 Jan 2026 00:46
URI:	https://oak.novartis.com/id/eprint/55018