Three routes to peripheral tolerance failure
Peripheral tolerance can fail through loss of regulatory T cell suppression, through weakened inhibitory receptor signaling that lowers the activation threshold, or through bystander activation in an inflamed environment. Each route removes a different restraint, but all three allow a self-reactive lymphocyte to receive the signals it needs to respond.
Bystander activation during infection
A lymphocyte specific for a self-antigen sits quietly in a tissue. A nearby infection drives intense local cytokine release. Those cytokines provide the costimulatory context the self-reactive cell lacked, and it activates without ever recognizing the pathogen. The infection triggered the response, but the response is not aimed at the pathogen.