Simplified model illustrating the hypothesis that Porphyromonas gingivalis -mediated citrullination triggers anti-citrulline autoimmunity in rheumatoid arthritis. Citrullination by P. gingivalis peptidylarginine deiminase (PAD) in the inflammatory context of periodontitis produces bacterial and host-derived citrullinated peptides to which the immune system mounts a humoral immune response with the production of peptidylcitrulline antibodies. Inflammation-induced citrullination by human PAD enzymes in the gingiva is also possible (dashed arrow). Tissue injury and inflammation in the joint lead to activation of human PAD enzymes and citrullination of host proteins, such as a-enolase, vimentin, fibrin(ogen), and collagen type II. Peptidylcitrulline antibodies bind citrullinated host and bacterial peptides, which may show molecular mimicry, and in genetically susceptible individuals (presence of the certain HLA alleles), intra- and intermolecular epitope spreading leads to a sustained immune response with the formation of high-affinity antibodies to host citrullinated proteins.