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Citrullination and autoimmune disease: 8th Bertine Koperberg meeting
  1. E R Vossenaar1,
  2. W H Robinson2
  1. 1Department of Biochemistry, Radboud University Nijmegen, Nijmegen, The Netherlands
  2. 2Division of Immunolgy and Rheumatology, Stanford University School of Medicine, Stanford, USA; Palo Alto Veterans Affairs Health Care System, Palo Alto, California, USA

https://doi.org/10.1136/ard.2005.045716

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    Citrullination, the process in which citrulline-containing proteins are formed, seems to have a role in several autoimmune diseases.1,2 Although citrulline is a common metabolite present throughout the human body, it is a non-standard amino acid, which means that it cannot be incorporated into proteins during protein synthesis. Citrulline-containing proteins can only be generated through post-translational modification of arginine residues, a reaction that is catalysed by peptidylarginine deiminase (PAD) enzymes.3

    At the 8th Bertine Koperberg meeting in Nijmegen, The Netherlands, held in March 2005, the way in which citrullination might be involved in the autoimmune diseases rheumatoid arthritis (RA) and multiple sclerosis (MS) was discussed.

    PAD ENZYMES, CITRULLINATION, AND ANTIBODIES TO CITRULLINATED PROTEINS

    Ger Pruijn (Nijmegen, The Netherlands) gave an excellent overview of the enzymes responsible for citrullination. Five, highly conserved isotypes of PAD enzymes exist in all mammalian species (PAD1–PAD4 and PAD6). The main difference between the isotypes is their tissue-specific expression. For RA and MS, PAD2 and PAD4 are the most interesting enzymes as both of them are expressed in the synovium and central nervous system (CNS). All PAD enzymes require high calcium levels for activity (about 10−5 mol/l). Because the intracellular calcium concentration in healthy cells is much lower (∼10−7 mol/l), the enzymes are only activated during events that lead to high calcium levels, like cell death, or late in the differentiation of skin cells (PAD1 and PAD3), as was explained by Michel Simon (Toulouse, France). Citrullination thus is believed to have an important role in several physiological processes, including the normal development of the myelin sheath and epidermis.

    The effect of citrullination on protein function was also discussed. Whereas arginine is a positively charged amino acid, citrulline is uncharged, and citrullination of proteins thus leads to a loss of net positive charge. As a result, the target proteins adopt an …

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