In pDCs, BTK-inhibition (BTKi) blocks the IFN-α production via TLR-9, but not via TLR-7. Upon TLR-7 stimulation, BTKi enhances the production of IFN-α by blocking the inhibitory BDCA-2 pathway. This might explain partially the failure of BTKi in SLE and is of interest for BTKi trials in multiple sclerosis.