Figure 2.

Potential mechanisms driving irAEs. (A) Activation of cytotoxic self-reactive T cells causes damage in off-target healthy tissues by extensive production of pro-inflammatory cytokines and/or direct attack. Activated autoreactive B cells may produce de novo auto-antibodies or increase the amount of pre-existing auto-antibodies. Antibodies bind to healthy tissues and cause inflammation and damage. (B) Clonal proliferation of virus-specific T cells may lead to excessive inflammation and destruction in the relevant organ and may be fatal. (C) Expansion of the T cell repertoire may cause T cells to attack off-target healthy tissues. (D) ICI treatment can lead to decreased number of FoxP3-expressing Treg cells and reprogramming of Treg cells, resulting in pro-inflammatory behavior. (E) Organ-specific expression of ICI targets can induce direct ICI binding followed by complement activation and antibody-mediated inflammation (type II hypersensitivity). (F) Genetic polymorphisms such as some HLA allele types, mutations of IC receptors and miRNAs are associated with the development of irAEs. (G) Microbiome composition (bacteria, metabolites, etc.) may cause aberrant activation of the immune system and increased production of inflammatory cytokines under ICI treatment.