The timing of intervention could be also crucial for B-cell targeting, as important changes have been reported in the B-cell compartment during T1D progression from aAb− to established T1D [102], involving modifications of the frequency of transitional and anergic B cells, as well as their responsiveness to IL-21 and B-cell receptor (BCR) signaling that are unique for each stage. This evidence concerns the gene IL21 and type 1 diabetes mellitus.