Citrullination of autoantigens implicates NETosis in the induction of autoimmunity

Abstract

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins thus are crucial questions for understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death called NETosis deserves attention because it requires the post-translational modification of histones and results in the extracellular release of chromatin. NETosis received its name from NET, the acronym given to Neutrophil Extracellular Trap. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4). The deiminated chromatin may function to capture or ‘trap’ bacterial pathogens, thus generating an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalised by host phagocytes during acute inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. Autoantibodies to deiminated histones are prevalent in Felty's syndrome patients and are present in systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). These observations clearly implicate histone deimination as an epigenetic mark that can act as an autoantibody stimulant.