RA can be triggered in the potential trigger sites (lung, oral, gut, et al.) by the interaction between the genes and environmental factors, which is characterized by the onset of self-protein citrullination resulting in the production of autoantibodies against citrullinated peptides. Lung exposure to noxious agents, infectious agents (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Epstein-Barr virus), gut microbiome, and dietary factors may induce the self-protein citrullination and maturation of ACPA. Citrullination is catalyzed by the calcium-dependent enzyme PAD, changing a positively charged arginine to a polar but neutral citrulline as the result of a post-translational modification. In RA, PAD can be secreted by the granulocyte and macrophage. ACPA occurs as a result of an abnormal antibody response to a range of citrullinated proteins, including fibrin, vimentin, fibronectin, Epstein-Barr Nuclear Antigen 1, α-enolase, type II collagen, and histones, all of which are distributed throughout the whole body. Many citrullination neoantigens would activate MHC class II-dependent T cells that in turn would help B cells produce more ACPA. The stage is also called loss of tolerance. RA rheumatoid arthritis, PAD peptidyl-arginine-deiminase, ACPA anti-citrullinated protein antibodies, RF rheumatoid factor.