TY  - JOUR
AU  - Naouar, Ikbel
AU  - Pangan, Andrei
AU  - Zuo, Michelle
AU  - Raza, Syed Ali
AU  - Champagne-Jorgensen, Kevin
AU  - Patel, Jyot
AU  - Wang, Angela
AU  - Pu, Annie
AU  - Ward, Lesley
AU  - Ahn, Jennifer S Y
AU  - Sayeed, Faizah N
AU  - Zhu, Jingwen
AU  - Pössnecker, Elisabeth
AU  - Spring, Shoshana
AU  - Sled, John G
AU  - Cenni, Bruno
AU  - Nuesslein-Hildesheim, Barbara
AU  - Browning, Jeffrey L
AU  - Pröbstel, Anne-Katrin
AU  - Reich, Daniel S
AU  - Gommerman, Jennifer L
AU  - Ramaglia, Valeria
TI  - Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury.
JO  - Nature immunology
VL  - 27
IS  - 1
SN  - 1529-2908
CY  - London
PB  - Springer Nature Limited
M1  - DZNE-2026-00022
SP  - 48 - 60
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Chemokine CXCL13: metabolism
KW  - Chemokine CXCL13: immunology
KW  - Gray Matter: immunology
KW  - Gray Matter: pathology
KW  - Gray Matter: metabolism
KW  - Humans
KW  - Mice
KW  - Encephalomyelitis, Autoimmune, Experimental: immunology
KW  - Encephalomyelitis, Autoimmune, Experimental: pathology
KW  - Meninges: immunology
KW  - Meninges: metabolism
KW  - Meninges: pathology
KW  - B-Cell Activating Factor: metabolism
KW  - B-Cell Activating Factor: immunology
KW  - Multiple Sclerosis: immunology
KW  - Multiple Sclerosis: pathology
KW  - Multiple Sclerosis: metabolism
KW  - Female
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Lymphotoxin-alpha: metabolism
KW  - Th17 Cells: immunology
KW  - Tertiary Lymphoid Structures: immunology
KW  - Tertiary Lymphoid Structures: pathology
KW  - B-Lymphocytes: immunology
KW  - Chemokine CXCL13 (NLM Chemicals)
KW  - B-Cell Activating Factor (NLM Chemicals)
KW  - CXCL13 protein, human (NLM Chemicals)
KW  - Lymphotoxin-alpha (NLM Chemicals)
KW  - Cxcl13 protein, mouse (NLM Chemicals)
KW  - TNFSF13B protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41482555
DO  - DOI:10.1038/s41590-025-02359-5
UR  - https://pub.dzne.de/record/283126
ER  -