Peptidylarginine Deiminase
Anti-cyclic citrullinated peptide antibodies (Anti-CCP-Abs)

Author: Gianpiero Pescarmona
Date: 18/02/2010


Heparin-dependent modification of the reactive center arginine of antithrombin and consequent increase in heparin binding affinity. 1997

citrullination target

Peptidylarginine deiminase 4 and citrullination in health and disease. 2010

  • PAD4 is the only enzyme catalyzing deimination with a nuclear localization signal.
  • PAD4 is upregulated by estrogens and involved in gene regulation.
  • PAD4 contributes to the generation of ACPA specific substrates and is itself a target of autoantibodies in RA.
  • PADI4 gene is associated with RA in Asians, not in Caucasians.
  • In spite of extensive deimination in the brain of MS patients
    • no autoantibodies to deiminated proteins are detected in MS.
    • no role of the PADI4 gene in susceptibility to MS have been so far described.

Citrullination as anti-thrombotic action?

J Biochem. 2008 Sep;144(3):393-8. Epub 2008 Jun 26.

Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization.
Nakayama-Hamada M, Suzuki A, Furukawa H, Yamada R, Yamamoto K.

Daiichi-Sankyo Co., Ltd., Shinagawa-ku, Tokyo 140-8710, Japan.

Citrullination is the post-translational modification of arginine residues by peptidylarginine deiminases (PADIs). Fibrinogen is one substrate of PADIs under physiological conditions. Fibrinogen is an important factor for blood coagulation and inducing inflammation. The citrullinated form of fibrinogen appears in rheumatoid arthritis synovial tissue together with the production of autoantibodies that target self-peptides containing citrulline. However, whether the function of fibrinogen changes after citrullination remains unclear. We found that citrullinated fibrinogen markedly impairs the function of thrombin-catalysed fibrin polymerization and also inhibits fibrin formation. Increased citrullinated fibrinogen might thus affect the balance between coagulation and fibrinolysis and alter antigenicity under physiological conditions. These data suggest that citrullination of proteins could physiologically change functions and subsequently generate pro-inflammatory conditions and autoimmune reactions.

PMID: 18583356 [PubMed - indexed

Clin Rheumatol. 2009 Jul;28(7):767-75. Epub 2009 Mar 10.
Cardiovascular disease is associated with extra-articular manifestations in patients with rheumatoid arthritis. 2009

The objective of this study was to examine the clinical and genetic variables associated with extra-articular rheumatoid arthritis (ExRA). This was a cross-sectional study in which 538 Northwestern Colombian patients with rheumatoid arthritis (RA) were included. Information about demographics and clinical characteristics including disease activity, inflammatory markers, co-morbidities, cardiovascular (CV) risk factors, history of familial autoimmunity and therapy was recorded. The presence of HLA "shared epitope" (SE) alleles and TNF gene polymorphism was assessed. A multivariate statistical analysis was performed. ExRA was found in 32% of the patients, of which nodulosis, Sjögren's syndrome, and lung involvement were registered in 21%, 9%, and 4% of patients, respectively. Patients with ExRA were older than patients without it and they presented longer disease duration as well. Thus, an association between disease duration and ExRA manifestations was also observed. Patients with ExRA presented significant higher titers of anti-CCP antibodies as compared to patients without ExRA. Hypertension and thrombosis were significantly associated with ExRA. Never having smoked constituted a protective factor against ExRA onset. Associations between ExRA and the presence of traditional CV risk factors were also found. Our results show that duration of RA, CV disease and high titers of anti-CCP antibodies are associated with ExRA in Colombian patients with RA, and highlight the importance of preventing smoking in those who are prone to develop autoimmune diseases including RA.

Open question

Is Prothrombin a suitable substrate for PD?

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