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There are many posttranslational modifications of proteins of which all are homeostatically important either to carry out a particular structural or functional role or to allow efficient recycling of the amino acid constituents. An important feature of the modified proteins is the acquisition of autoantigenicity. That notion should have been recognized for years with the modifications of immunoglobulin G that constitute new targets for rheumatoid factors. Citrullination or the deimination of arginine residues in proteins creates epitopes that are targeted by rheumatoid autoantibodies with a diagnostic sensitivity and specificity of 40% to 70% and 92% to 99%, respectively. The how, when, and why of the responsible break in tolerance are largely speculative but apoptosis, multiple genetic and environmental influences are likely required. Identifying citrullinated proteins as autoantigens has resulted in new diagnostic and prognostic autoantibody markers for RA and studying the citrullination process and its nature and role in cell biology has provided new insights into its pathogenesis.