Autoantibodies and T Cells Target Citrullinated and Homocitrullinated Antigens in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a prevalent form of inflammatory arthritis in which post-translational modifications are known to play a major role in the loss of tolerance. This review summarizes current knowledge of the role that such modifications play in the disease. Most individuals with RA have antibody responses directed against citrullinated and/or carbamylated self-antigens, but additional modifications are under active investigation. Post-translational modifications can alter the primary protein sequence, increasing binding to HLA molecules and recognition by T cells, and can generate new epitopes that are recognized by autoantibodies. They can also perturb protein structure and alter protein processing, enhancing presentation of cryptic epitopes. Finally, these modifications can alter protein function, potentially undermining cellular identity and function. Potentiation of post-translational modifications has been directly linked to environmental exposures that are epidemiologically tied to RA risk. The immunogenic effects of protein modification are associated with key variants that confer genetic risk for RA. Notably, immune assays designed to measure antibody recognition and monitor T cell responses directed against citrullinated and carbamylated antigens have emerged as useful biomarkers of disease risk and activity. The pathways of protein citrullination and carbamylation are also important targets for potential preventative and curative therapies.