Host-driven citrullination of extracellular vesicle-derived microbial proteins links P orphyromonas gingivalis to rheumatoid arthritis

Background

Rheumatoid arthritis (RA) is closely linked to citrullinated antigens and HLA-DRB1 risk alleles, yet the origin of immunogenic citrullinated peptides remains incompletely understood. While Porphyromonas gingivalis has been implicated in RA through its bacterial peptidylarginine deiminase (PPAD), previous studies using PPAD-deficient P. gingivalis in mouse RA models reported that PPAD deletion did not attenuate disease development, suggesting the existence of additional RA-promoting mechanisms. Here, we computationally evaluate a complementary mechanism in which host peptidylarginine deiminase 4 (PADI4) may modify P. gingivalis-derived proteins, generating microbial neoantigens with preferential presentation by RA-associated HLA alleles.