Anti‐Modified Protein Antibodies in Rheumatoid Arthritis: Pathogenic, Protective, or Passive Bystander?

ABSTRACT The presence of anti‐modified protein antibodies (AMPA) is a hallmark of rheumatoid arthritis (RA). AMPA recognize post‐translationally modified proteins and are cross‐reactive. AMPA include anti‐citrullinated protein antibodies (ACPA), anti‐carbamylated protein antibodies (anti‐CarP), and anti‐acetylated protein antibodies (AAPA). These autoantibodies can be detected years before disease onset and are associated with disease development and progression. Moreover, AMPA have been associated with genetic and environmental risk factors in RA, including human leukocyte antigen (HLA) alleles, smoking, and microbial exposure. Consequently, AMPA have been implicated in RA pathogenesis, yet their exact role remains unclear. ACPA may exert pathogenic, pro‐inflammatory effects through immune complex formation, Fc gamma receptor binding on macrophages, complement activation, and increased neutrophil extracellular trap (NET) formation. Additionally, ACPA have been linked to bone loss and pain induction in mice. However, ACPA may also have protective effects through inhibition of NET release, increased NET clearance, and Fc gamma receptor binding on macrophages. These findings indicate that AMPA may have diverse functions in RA, with both pathogenic and protective effects, whereas some ACPA may not display functional activity. Further studies on AMPA characteristics and mechanisms underlying the pathogenic and protective effects may improve the understanding of the role of AMPA in RA.