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.