Host-driven citrullination of extracellular vesicle-derived microbial proteins links P orphyromonas gingivalis to rheumatoid arthritis.
- 1Department of Microbiology and Immunology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
- 2Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
- 3Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Im-munology (CFAI), Graduate School of Agricultural Science, Tohoku University, Japan.
Abstract
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.Methods
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.Results
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.Conclusions
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.
Related
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- Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
BibTeX
@article{cheng2026hostdriven,
title = {{Host-driven citrullination of extracellular vesicle-derived microbial proteins links P orphyromonas gingivalis to rheumatoid arthritis.}},
author = {Xuefei Cheng and Weichen Gong},
journal = {Journal of oral microbiology},
year = {2026},
month = oct,
doi = {10.1080/20002297.2026.2751754},
url = {https://europepmc.org/article/MED/42910306},
note = {CC BY},
}
RIS
TY - JOUR
TI - Host-driven citrullination of extracellular vesicle-derived microbial proteins links P orphyromonas gingivalis to rheumatoid arthritis.
AU - Xuefei Cheng
AU - Weichen Gong
PY - 2026
DA - 2026/10/20
JO - Journal of oral microbiology
DO - 10.1080/20002297.2026.2751754
UR - https://europepmc.org/article/MED/42910306
AB - 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.Methods 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.Results 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.Conclusions 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.
SN - 2000-2297
ER -