Anti-citrullinated peptides as autoantigens in rheumatoid arthritis—relevance to treatment

• ACPAs are associated with the HLA-DRB1 shared epitope(SE) and account for the association of RA with HLA-DRB1SE.
• Citrullinated antigens are recognized not only by B cells but also by T cells.
• Citrullinated proteins can induce arthritis in HLD-DR4 trangenic mice.
• ACPAs induce TNF production by macrophages & osteoclastogenesis & promote the formation of neutrophil extracellular traps.
• Rituximab and, most likely, abatacept are best therapy for ACPA(+) RA patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). Citrulline derives from arginine by peptidyl arginine deiminases, and ACPAs are directed against different citrullinated antigens, including fibrinogen, fibronectin, α-enolase, collagen type II, histones. ACPAs are present in two thirds of RA patients have higher specificity than RF for RA, and are associated with joint radiographic damage and extra-articular manifestations and they are detected years before the onset clinical arthritis. Recent studies suggest that citrullinated antigens are most likely arthritogenic autoantigens in RA. ACPA production is associated with the HLA-DRB1 shared epitope (HLA-DRB1 SE) and accounts for the well-known RA-HLA-DRB1 SE association, as T cells recognize citrullinated peptides. Smoking and periodontitis, known environmental risk factors for RA promote protein citrullination and ACPA production. Cirullinated proteins are capable of inducing arthritis in transgenic mice carrying HLA-DRB1 SE genes, and ACPAs induce macrophage TNF-α production, osteoclastogenesis and complement activation. They also induce the formation of neutrophil extracellular traps (NETs). NETs, increased in RA, are a source of citrullinated autoantigens in RA and induce fibroblast interleukin-8 production. This knowledge is likely to have therapeutic implications, as there is a need of matching therapy with patient profile. Abatacept, a T cell activation modulator, is the best therapy for ACPA(+) RA patients, although clinical data are sparse at present. Rituximab, a monoclonal antibody that depletes B cells, is also the best therapy for ACPA(+) RA patients, and clinical data support this view.