In fact, although the mechanism of ‘central tolerance’ eliminates most of the lymphocytes which could be activated by self-antigens, self-reactive lymphocytes always exist in the natural immune repertoire but do not elicit remarkable autoimmune diseases, due partly to the lack of activation signal (also termed as ‘second signal’) and the action of negative checkpoints such as PD-1/PD-L1, termed ‘peripheral tolerance’, thus keeping a balance between preventing infection and preventing autoimmunity. Here, CD274 is linked to autoimmune disease.