BTK Inhibition Shows Reduction in Gray Matter Lesions Caused by MS

Gray matter lesions in MS are poorly understood, and there are currently no effective treatments that target the cortical demyelination, neuron loss, and microglial activation that drive disease progression. Current evidence shows that gray matter lesions are associated with B cell-rich tertiary lymphoid tissues (TLTs), which drive localized inflammation, and that Bruton’s tyrosine kinase (BTK) mediates intracellular B cell signaling. A study by Ikbel Naouar used mice with a disease similar to MS, called experimental autoimmune encephalomyelitis (EAE), and treated them with Remibrutinib (LOU064), a BTK inhibitor, to investigate how gray matter lesions develop and whether BTK could be a potential therapeutic target.

Results showed that mice treated with the BTK inhibitor had fewer and smaller TLTs in the brains of both early onset and aged EAE mice, which also reduced the number of gray matter lesions compared to controls. In addition, the study showed that a higher ratio of CXCL13:BAFF proteins, hypothesized to work in opposition of each other, is associated with TLT formation and gray matter lesions in EAE mice and MS patients, while a lower ratio improved by the BTK inhibitor shows less gray matter injury. Further research is needed to clarify how BTK inhibition affects downstream signaling, which will help us better understand how gray matter lesions develop and whether targeting BTK could be an effective treatment for MS.

BTKi treatment in EAE mice compared to controls. Left shows that BTKi-treated mice have less gray matter lesions compared to controls in brain scans. Right graphs show the number and size of TLTs in BTKi-treated vs. controls.

Reference: 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., Spring, S., Sled, J. G., Cenni, B., Nuesslein-Hildesheim, B., Browning, J. L., Pröbstel, A. K., … Ramaglia, V. (2026). Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury. Nature Immunology, 27(1), 48–60. https://doi.org/10.1038/s41590-025-02359-5