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

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.

We developed a computational framework integrating known PADI4 and PPAD substrate preferences with MHC-II antigen presentation prediction. Human proteins were first stratified based on their susceptibility to PADI4 and/or PPAD-mediated citrullination, and their presentation profiles across RA risk-associated (HLA-DRB1*04:01 and 04:04) and protective (HLA-DRB1*13:01 and 13:02)alleles were analyzed through MHC-II binding prediction.

This analysis revealed distinct presentation signatures, including (a) global risk enrichment, (b) high-affinity binding bias, (c) characteristic allelic presentation ratios. Application of these three features led to the identification of five candidate proteins with potential relevance to RA risk, including gingipain R1 and four outer membrane proteins.

These findings propose a hypothesis that host PADI4-mediated citrullination of P. gingivalis proteins may represent an additional mechanism contributing to P. gingivalis-associated acceleration of RA pathogenesis.