Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

Structural Basis of Cross‐Reactivity of Anti–Citrullinated Protein Antibodies

“…The crystal structures of 2 murine ACPAs, ACC1 (PDB accession code 5mu0) and ACC4 (PDB accession code 2w65) in complex with citrullinated peptides, have been reported previously . ACC1 is a highly arthritogenic antibody that targets the citrullinated C1 epitope on CII but also cross‐reacts with several noncitrullinated epitopes on native CII, as well as with some classic citrullinated peptides such as CCP‐2 and CCP‐1.…”

“…To characterize the binding profiles of ACPAs, we focused on several reported monoclonal ACPAs (a complete list is provided in Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40698/abstract). Two of these autoantibodies (namely, E4 and F3) had N ‐linked glycans in the variable domains that could modulate their binding profiles to citrullinated antigens .…”

“…In addition, we analyzed 2 ACPAs (ACC1 and ACC4) that were generated from mouse serum. These have been shown to be arthritogenic, based on findings of their cross‐reactivity with triple helical CII (ACC1) or with a citrullinated peptide derived from CII (ACC4) .…”

“…So far, only a subtype of ACPAs cross‐reactive with joint cartilage has been shown to be able to induce arthritis upon direct injection into mice . Interestingly, Fc glycan sialylation of these antibodies transforms them into protective antibodies .…”

Germinal Center B Cells Are Essential for Collagen‐Induced Arthritis

“…Interestingly, antibodies reacting to CII (AC2A) also arise in a subset of RA patients and are in particular produced in affected joints . Although present in a minor subset of patients, it is important to note that the only antibodies that have so far been shown to induce arthritis are reactive with joint cartilage, including ACPAs that cross‐react with CII . The AC2A antibodies in RA are isotype‐switched, but there is currently no evidence that they are extensively somatically mutated, similar to the mouse model of CIA .…”