Physiological pathways of PAD activation and citrullinated epitope generation

Abstract

The peptidylarginine deiminase (PAD) enzymes hydrolyze arginine residues to create the nonnative amino acid citrulline (a process called citrullination or deimination). Five PAD enzymes (1, 2, 3, 4, 6) have been identified, and they exhibit fairly restricted tissue expression patterns. The conversion of arginine to citrulline (referred to as citrullination or deimination) results in only a small change in molecular mass (less than 1 Da) and a loss in a positive charge, which can have dramatic consequences on protein structure and protein-protein interactions. Since citrullination can lead to profound changes in protein function, it is not surprising that citrullination and the activity of the PAD enzymes has been implicated in many diseases, such as rheumatoid arthritis (RA), multiple sclerosis, Alzheimer's disease, inflammatory bowel disease, psoriasis, and cancer. This chapter provides a general overview of the PAD enzymes and their known functions. Plasma and synovial biopsy specimen from patients with rheumatoid arthritis contain high levels of citrullinated proteins, and, in fact, rheumatoid patients often develop immune reactivity to citrullinated proteins. Here, we also discuss possible physiological pathways that may contribute to the generation of citrullinated self-antigens, which could then prime the development of anti-citrulline peptide autoantibodies in rheumatoid arthritis.