A new study shows that patients deficient in autoimmune regulator (AIRE) have high-affinity neutralizing antibodies against type 1 interferons (IFNs), levels of which inversely correlate with type 1 diabetes mellitus (T1DM). Serum was collected from 81 AIRE-deficient patients and directed against a protein array displaying ∼9,000 proteins. Most patients displayed autoreactivity to ∼100 self-proteins, many of which were cytokines, IFNs in particular. Patient-derived IFN-specific mAbs inhibited IFN-dependent responses in vitro and IFN-induced pathologies in mice. Moreover, in patient studies, antibody-mediated neutralization of IFNα subtypes was associated with protection against T1DM. The findings suggest that naturally occurring human autoantibodies have therapeutic potential and that targeting IFNs could be an effective strategy to treat T1DM.