Autoimmunity and management of the Immune-related adverse effects of the Immune Checkpoint inhibitors

The immune checkpoint molecules such as CTLA-4 and PD-1 are involved in the tolerance mechanisms preventing the immune system to react against the self-antigens. When these receptors expressed on the lymphocyte membrane, bind to their ligands, they induce a negative signal to the cell which becomes unable to be completely activated in the presence of its antigen. In a context of tumor, the infiltrating T cells are frequently exhausted due to the expression of CTLA-4 and PD-1 ligands by the microenvironment impairing the antitumoral immunity. The use of antagonistic antibodies targeting these receptors or their ligands (called checkpoint inhibitors) aims to block their interaction unbalancing the negative regulation of the antitumoral lymphocytes. However, this effect affects all lymphocytes and may also disrupt the negative regulation of the peripheral autoreactive lymphocytes. Thus, a significant proportion of patients treated by these molecules develop immune-related symptoms affecting different tissues and organs due to lymphocyte activation. These symptoms are called immune-related adverse events (irAEs). This article aims to summarize the scientific data demonstrating the implication of these molecules in the tolerance mechanisms and in the autoimmune diseases. It also reports on the IrAEs observed in treated patients and gives an outline of guidelines to monitor and manage these patients.