An essential step in the formation of ACPA autoantibodies is the citrullination of self-protein by peptidyl arginine deiminase (PAD), a family of enzymes that modify proteins by converting arginine to citrulline and conferring antigenic potential.1-3

  • In susceptible individuals, tolerance to citrullinated self-proteins breaks down and these PAD-modified self-proteins become self-antigens, driving T-cell activation, differentiation and consequent inflammation.1,4
  • T-cells in turn promote B-cell maturation and activation of B cells, with ultimate production of autoantibodies to citrullinated self-proteins, which may appear many years prior to onset of disease symptoms.1,4,5
  • Circulating ACPA autoantibodies that enter the joint as well as those generated within the joint induce local inflammation through the formation of immune complexes with PAD-citrullinated proteins.4,6
  • PAD-induced anti-citrullinated protein autoantibodies (ACPAs) have been associated with more aggressive autoimmune disease with a poorer prognosis.3,5

Peptidyl Arginine Deiminase (PAD)


  1. Klareskog L, Rönnelid J, Lundberg K, et al. Ann Rev Immunol. 2008;26:651-75.
  2. Gudmann NS, Hansen NUB, Jensen ACB, et al. Autoimmunity. 2015;48(2):73-79.
  3. Mowen KA, David M. Nature Immunol. 2014;15(6):512-520.
  4. Catrina AI, Ytterberg J, Reynisdottir G, et al. Nature Reviews/Rheum. 2014;10:645-653.
  5. loan-Facsinay A, el-Bannoudi H, Scherer HU, et al. Ann Rheum Dis. 2011;70:188-193.
  6. Spengler J, Lugonja B, Ytterberg AJ, et al. Arthritis & Rheumatol. 2015;67(12):3135-3145.