Full Papers
Immune responses targeting homocitrullinated peptides drive rheumatoid arthritis-like pathology in HLA-DR4 transgenic mice
G. Buckley1, S. Saunders2, E. Cairns3, L. Barra4
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada.
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada.
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON; and Department of Medicine/Rheumatology, The University of Western Ontario, London, ON, Canada.
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON; Department of Medicine/Rheumatology, The University of Western Ontario, London, ON; and Department of Epidemiology and Biostatistics, The University of Western Ontario, London, ON, Canada. lillian.barra@sjhc.london.on.ca
CER19823
Full Papers
PMID: 42873707 [PubMed]
Received: 18/02/2026
Accepted : 13/07/2026
In Press: 06/10/2026
Abstract
OBJECTIVES:
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. A hallmark feature of RA is the presence of anti-citrullinated protein autoantibodies (ACPAs), which have been extensively studied in disease pathogenesis. The development of these autoantibodies is strongly associated with the expression of HLA-DR4, containing the shared epitope. More recently, anti-homocitrullinated protein autoantibodies (AHCPAs) have also been implicated in RA and demonstrate a similar genetic association. Therefore, this study aimed to evaluate the role of homocitrulline immune responses in RA pathogenesis.
METHODS:
HLA-DR4 transgenic (DR4tg) and C57Bl/6 (B6) mice were immunised with a synthetic homocitrullinated peptide (HomoCitJED) or PBS followed by a booster 21 days later. Beginning on day 75 post-primary immunisation mice received knee intra-articular (i.a.) injections of HomoCitJED once a week for three consecutive weeks. Swelling post i.a. injection was measured using digital calipers. IgG antibodies against citrullinated/homocitrullinated peptides/proteins were measured using enzyme-linked immunosorbent assay (ELISA). Knees were sectioned and analysed for histopathological damage and citrullinated/homocitrullinated protein levels.
RESULTS:
HomoCitJED immunised DR4tg mice exhibited significantly greater swelling and incidence of anti-HomoCitJED and anti-homocitrullinated fibrinogen IgG autoantibodies. Additionally, 30% had responses against CitJED, a synthetic citrullinated peptide. HomoCitJED immunised DR4tg mice also experienced greater total histopathological damage; however, the immunisations/injections did not affect citrullinated/homocitrullinated protein levels in the joint.
CONCLUSIONS:
Homocitrulline-specific immune responses can induce RA-like disease in DR4tg mice, supporting the pathogenic role of AHCPAs in RA.
