Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by synovial inflammation and destruction of joints. Over 20 years ago, tumour necrosis factor alpha (TNF alpha) was identified as a key player in a cytokine network, whose multifunctional effects could account for both the inflammation and destruction in RA. The remarkable efficacy of TNF inhibitors in the treatment of RA has resulted in extensive research addressing the regulation of TNF alpha production responsible for this excessive production. The discovery of autoimmunity to citrullinated protein/peptide antigens (ACPA) has led the concept that ACPA may be the essential link between disease susceptibility factors and the production of TNF alpha, which ultimately accounts for the disease phenotype. In this review we will consider (1) the mechanisms of citrullination, both physiological and pathological, (2) how known genetic and environmental factors could drive this peculiar form of autoimmunity and (3) how the immune response could lead to excessive production of TNF alpha by the synovial cells and ultimately to the disease phenotype (Fig. 1). (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.