Journal Article

DZNE-2026-00022

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury.

Naouar, I. ; Pangan, A. ; Zuo, M. ; Raza, S. A. ; Champagne-Jorgensen, K. ; Patel, J. ; Wang, A. ; Pu, A. ; Ward, L. ; Ahn, J. S. Y. ; Sayeed, F. N. ; Zhu, J. ; Pössnecker, E.DZNE* ; Spring, S. ; Sled, J. G. ; Cenni, B. ; Nuesslein-Hildesheim, B. ; Browning, J. L. ; Pröbstel, A.-K.DZNE* ; Reich, D. S. ; Gommerman, J. L. ; Ramaglia, V.

2026
Springer Nature Limited London

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Please use a persistent id in citations: doi:10.1038/s41590-025-02359-5

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.

Keyword(s): Animals (MeSH) ; Chemokine CXCL13: metabolism (MeSH) ; Chemokine CXCL13: immunology (MeSH) ; Gray Matter: immunology (MeSH) ; Gray Matter: pathology (MeSH) ; Gray Matter: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: immunology (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: pathology (MeSH) ; Meninges: immunology (MeSH) ; Meninges: metabolism (MeSH) ; Meninges: pathology (MeSH) ; B-Cell Activating Factor: metabolism (MeSH) ; B-Cell Activating Factor: immunology (MeSH) ; Multiple Sclerosis: immunology (MeSH) ; Multiple Sclerosis: pathology (MeSH) ; Multiple Sclerosis: metabolism (MeSH) ; Female (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Lymphotoxin-alpha: metabolism (MeSH) ; Th17 Cells: immunology (MeSH) ; Tertiary Lymphoid Structures: immunology (MeSH) ; Tertiary Lymphoid Structures: pathology (MeSH) ; B-Lymphocytes: immunology (MeSH) ; Chemokine CXCL13 ; B-Cell Activating Factor ; CXCL13 protein, human ; Lymphotoxin-alpha ; Cxcl13 protein, mouse ; TNFSF13B protein, human

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Contributing Institute(s):

1. Clinical Neurology and Neuroimmunology (AG Pröbstel)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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