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Unlocking the “PAD” lock on rheumatoid arthritis
  1. P J Utz1,
  2. M C Genovese1,
  3. W H Robinson1,2
  1. 1Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
  2. 2GRECC, VA Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, California, USA
  1. Correspondence to:
    Dr P J Utz
    Stanford University, CCSR Building, Room 2215A, 269 Campus Drive, Stanford, CA 94305, USA;

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Perhaps a panel of antigens containing citrulline may explain RA: many questions remain

Rheumatoid arthritis (RA) affects about 1% of the world population, yet the driving antigen(s) remain unidentified. A number of different antigens have been proposed to have a fundamental role in RA, including antibodies bound by rheumatoid factor (RF), collagen, BiP, Sa, and many others (reviewed by Rantapää-Dahlqvist et al1). The field has been revolutionised by the discovery that antigens containing arginine residues that have been deiminated to form citrulline are prominent targets of autoantibodies in RA.2,3 Their detection forms the basis of several assays that are now standard diagnostic tests in rheumatology clinics world wide. The goal of this editorial is to provide a brief history of the discovery of citrullinated antigens in RA, a review of what is known about the enzymes (peptidylarginine deiminases, PADs) involved in the catalysis of a reaction that forms citrulline, and a roadmap of future areas for research.


The history of citrullinated antigens is one that is particularly important for students of rheumatology to review, because the initial discovery was largely overlooked and rediscovered on several different occasions over the ensuing four decades. In 1964, in the Annals of the Rheumatic Diseases, a search for cell and tissue substrates containing antigens that could be bound by autoantibodies from patients with RA found that granules from differentiating buccal mucosal cells expressed such an autoantigen. The autoantibody system was termed “antiperinuclear factor”.4 A similar screen performed 15 years later showed that rat oesophagus was an ideal and more easily studied substrate for detection of these serum autoantibodies, and these were named “antikeratin antibodies”.5 This work went largely unnoticed until nearly another 20 years had passed, when two European groups independently demonstrated that the target of both antiperinuclear …

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