Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury
Year: 2026
Type: article
Abstract: In people living with multiple sclerosis (pwMS), brain leptomeningeal immune aggregates associate with subpial cortical pathology and disease progression, but the mechanism leading to this pathology is unknown. Moreover, biomarkers for brain leptomeningeal inflammation, which is very difficult to image, are lacking. In a passive model of experimental autoimmune encephalomyelitis (EAE) induced by adoptive transfer of Th17 cells into young SJL/J mice we used a selective covalent inhibitor of Bruton’s tyrosine kinase (BTKi) to identify the circuitry that drives leptomeningeal inflammation. We found that BTK inhibition reduced the formation of leptomeningeal B cell-rich aggregates and diminished demyelination and axonal loss in the subpial cortex concomitant with a lower ratio of BAFF/CXCL13 in the leptomeninges. Mechanistically, treatment with BTKi interfered with the expression of Lymphotoxin beta Receptor ligands, and co-treatment with a LTβR agonist abrogated the therapeutic benefits of BTKi. We also observed a low BAFF/CXCL13 ratio in CSF collected post-mortem from pwMS that exhibited high levels of leptomeningeal inflammation from matching brain tissue, compared to pwMS with low leptomeningeal inflammation. Together, our data demonstrate that B cell-rich leptomeningeal aggregates in SJL/J adoptive transfer EAE mice are driven by the lymphotoxin pathway resulting in a lower BAFF/CXCL13 ratio in the leptomeninges. BAFF/CXCL13 ratios in the CSF could serve as a potential surrogate marker for B cell-rich leptomeningeal aggregates, providing a better means to stratify and monitor MS patients receiving brain-penetrant drugs such as BTKi.
Source: Nature Immunology
Authors: Ikbel Naouar, Andrei Pangan, Michelle Zuo, Syed Ali Raza, Kevin Champagne-Jorgensen, Jyot Patel, Angela Wang, Annie Pu, Lesley Ward, Jennifer S. Y. Ahn, Faizah N. Sayeed, Jingwen Zhu, Elisabeth Pössnecker, Shoshana Spring, John G. Sled, Bruno Cenni, Barbara Nuesslein-Hildesheim, Jeffrey L. Browning, Anne-Katrin Pröbstel, Daniel S. Reich, Jennifer L. Gommerman, Valeria Ramaglia
Institutions: University of Toronto, National Institutes of Health, National Institute of Neurological Disorders and Stroke, University of Bonn, University of Basel, University Hospital Bonn, German Center for Neurodegenerative Diseases, University Hospital of Basel, Hospital for Sick Children, Novartis (Switzerland), Novartis Institutes for BioMedical Research, Boston University, University Health Network, Krembil Brain Institute
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7117977386