Conditional deletion of the multiple sclerosis susceptibility gene ATXN1 identifies cell‐autonomous effects in the B‐cell compartment

Increasing evidence supports a mechanistic role for B cells in the pathogenesis of the autoimmune disorder multiple sclerosis (MS). We previously documented that the MS risk gene ataxin‐1 ( ATXN1 ) modulates key B‐cell functions and the severity of the MS disease model experimental autoimmune encephalomyelitis (EAE). ATXN1 encodes the polyglutamine protein ataxin‐1, which works in the cell nucleus as a corepressor of gene transcription. However, considering the ubiquitous expression of the ataxin‐1 protein and the limitations of global Atxn1 ‐null mouse models, the exact contribution of ataxin‐1 to B‐cell functioning and the overall EAE phenotype is not completely understood. To fill this gap, here we employed CRISPR‐mediated genomic editing to develop the first conditional‐knockout mouse line lacking ataxin‐1 in the B‐cell compartment. Using this novel in vivo model, we demonstrated that ataxin‐1 regulates B‐cell proliferation and activation in a cell‐autonomous fashion, and decreases the activation of T cells and monocytes through indirect mechanisms. We also found that depleting ataxin‐1 in B cells affects cytokine and immunoglobulin release in response to encephalitogenic challenges, but it is insufficient to modify the trajectory and neuropathology of the EAE model. Altogether, these results pinpoint a complex regulatory role for ataxin‐1 in autoimmune demyelination involving multiple cellular targets.