OBJECTIVE: Anticitrullinated protein/peptide antibodies (ACPA) are implicated in 
rheumatoid arthritis (RA) pathogenesis and linked to the shared epitope (SE). 
Citrulline modification is very similar to a different modified amino acid, 
homocitrulline. We investigated antihomocitrullinated protein/ peptide antibody 
(AHCPA) specificity for RA, whether ACPA were also able to bind 
homocitrullinated targets, and whether the SE could accommodate 
homocitrullinated peptide.
METHODS: Homocitrullinated fibrinogen was used to screen sera from patients with 
RA, psoriatic arthritis, and systemic lupus erythematosus, and healthy subjects 
for AHCPA using ELISA. Homocitrullination sites on fibrinogen were identified by 
mass spectrometry. ACPA were affinity-purified using a synthetic citrullinated 
peptide and tested for binding to homocitrullinated protein/peptide. Inhibition 
of antihomocitrullinated fibrinogen antibody binding was examined. 
Homocitrullinated peptide interaction with the SE was studied using computer 
modeling.
RESULTS: IgG antihomocitrullinated fibrinogen antibodies were found specifically 
in 49% of patients with RA. Enrichment of ACPA by affinity purification from 5 
patients with RA also enriched AHCPA. Serum AHCPA was inhibited by citrullinated 
fibrinogen and more significantly by homocitrullinated fibrinogen. Computer 
modeling indicated that the SE could accommodate a homocitrullinated peptide 
without steric hindrance. Mass spectrometry identified that 89/103 lysines of 
fibrinogen could be homocitrullinated, and 5 peptides that could be both 
citrullinated and homocitrullinated and are predicted to bind the SE.
CONCLUSION: Antihomocitrullinated fibrinogen antibodies are specific to RA. The 
presence of AHCPA coincides with ACPA, and AHCPA copurifies with ACPA in 
affinity purification and is inhibited by citrullinated and homocitrullinated 
antigens. Thus AHCPA and ACPA are frequently cross-reactive and 
homocitrullinated proteins/peptides may bind the SE.