BTK inhibition prevents microglia-mediated demyelination induced by multiple sclerosis patient antibodies

Here, we developed an in vivo model of MS using patient-derived, myelin-targeting recombinant antibodies to induce rapid focal demyelination in the mouse cortex that depended on epitope specificity and Fc gamma receptor and complement activity. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin sheaths driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature.

Parallel changes were observed in MS lesions, where microglia closely interacted with intact myelin sheaths and similar genes were upregulated. Prophylactic administration of a brain-penetrant inhibitor of Bruton’s tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in demyelination and support BTK inhibition as a therapeutic strategy to modulate microglial behavior to prevent demyelination.