Cross-reactivity of anti-modified protein antibodies in rheumatoid arthritis

This review comprehensively discusses the cross-reactivity of autoantibodies against modified proteins (AMPAs), the hallmark of rheumatoid arthritis (RA). We found that regardless of tissue sources, subtypes, or isotypes of B cells, AMPAs show high cross-reactivity within and across antigens undergoing citrullination, carbamylation, lysine-acetylation or ornithine-acetylation. The cross-reactive patterns of AMPAs display clonal and individual heterogeneity. Variations in the antibody reactivity to different modified antigens in RA are due to the diverse cumulative effects of cross-reactive profiles of AMPA clones. 'Shared motifs', as short motifs composed of one core modified residue with one or two flanking amino acids, are essential for AMPA cross-reactivity. AMPAs likely undergo affinity maturation towards shared motifs, during which their cross-reactivity to citrullinated antigens was increased, so collaterally was their cross-reactivity to other modifications due to structural similarities between modified residues. Cross-reactivity could aid the activation of AMPA B cells by facilitating T-cell signals from various modified antigens, direct pathogenic effects to tissues where modified antigens accumulate, and drive the clearance of in vivo modified antigens.