Although loss of either Itch or its functional partner E3, such as WWP2 or Cbl-b, in T cells had minimal to no overt effects on the spontaneous development of autoimmunity and inflammation in comparison with the combined loss of two E3s, it still remains elusive as to whether there is a functional compensation for Itch deficiency by another E3 ligase(s), in particular, the other NEDD4 E3s that share a structural homology with Itch. The gene discussed is ITCH; the disease is Autoimmunity.