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.