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The following is a summary of “Recognition of glycine versus non-glycine citrulline motifs dictates the HLA class II association of anti-citrullinated protein antibodies – insights from autoantibody profiling of 6900 Scandinavian rheumatoid arthritis patients,” published in the March 2025 issue of American College of Rheumatology by Alm et al. 

Anti-citrullinated protein antibodies (ACPA) in Rheumatoid arthritis (RA) bind citrulline-amino acid motifs, leading to diverse antibody profiles. Their targets vary across patients. 

Researchers conducted a retrospective study on ACPA patterns by citrulline motifs, analyzing RA risk factors HLA-DRB1 shared epitope (SE) alleles and smoking history.  

They measured rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP2) isotypes, 15 anti-Cit-, and 4 anti-Carb/Acet-peptide-IgG in 6,907 patients with RA using fluoroenzyme immunoassay and a multiplex solid-phase microarray. HLA-DRB1 SE alleles were imputed from SNP genotyping data. 

The results showed that single-citrulline peptides from 4 multi-citrulline peptides (Cit Fibα_36-50, Cit Fibβ_60-74, Cit TNC5, Cit Vim_60-75) had differential binding, confirming citrulline-motif recognition. About 4 citrulline-peptides (Cit Fibβ_36-52, Cit Fibβ_60-74-Cit3, Cit Fil_307-324, Cit Vim_60-75-Cit1) captured 97% of patients with IgG anti- CCP2+. ACPA, anti-Carb/Acet, and RF subsets differed in ACPA composition and disease activity but not comorbidities. Overlapping ACPA patterns emerged, but only non-glycine citrulline-motif ACPA associated with HLA-SE alleles. Among patients with IgG anti-CCP2+, 90% with only high non-glycine ACPA carried HLA-SE alleles, versus 67% with glycine-motif ACPA (OR=4.5). Smoking is associated with IgA and glycine-motif ACPA. 

Investigators found that HLA-SE alleles were primarily associated with ACPA to non-glycine citrulline-motifs, highlighting ACPA T-cell dependence. The etiological significance of ACPA targeting different protein structures remained unknown. 

Source: acrjournals.onlinelibrary.wiley.com/doi/abs/10.1002/art.43161