The conversion of an arginine residue in a protein to a citrulline residue, a 
reaction carried out by enzymes called peptidylarginine deiminases (PADs), is 
rather subtle. One of the terminal imide groups in arginine is replaced by 
oxygen in citrulline, thus resulting in the loss of positive charge and the gain 
of 1 dalton. This post-translational modification by PAD enzymes is conserved in 
vertebrates and affects specific substrates during development and in various 
mature cell lineages. Citrullination offers a unique perspective on autoimmunity 
because PAD activity is stringently regulated, yet autoantibodies to 
citrullinated proteins predictably arise. Autoantigens recognized by 
anti-citrullinated protein antibodies (ACPA) include extracellular proteins such 
as filaggrin, collagen II, fibrinogen, and calreticulin; membrane-associated 
proteins such as myelin basic protein; cytoplasmic proteins such as vimentin and 
enolase; and even nuclear proteins such as histones. Some ACPA are remarkably 
effective as diagnostics in autoimmune disorders, most notably rheumatoid 
arthritis (RA). Several ACPA can be observed before other clinical RA 
manifestations are apparent. In patients with RA, ACPA may attain a sensitivity 
that exceeds 70 % and specificity that approaches 96-98 %. The biological 
context that may account for the induction of ACPA emerges from studies of the 
cellular response of the innate immune system to acute or chronic stimuli. In 
response to infections or inflammation, neutrophil granulocytes activate PAD, 
citrullinate multiple autoantigens, and expel chromatin from the cell. The 
externalized chromatin is called a neutrophil extracellular "trap" (NET). 
Citrullination of core and linker histones occurs prior to the release of 
chromatin from neutrophils, thus implicating the regulation of citrullinated 
chromatin release in the development of autoreactivity. The citrullination of 
extracellular autoantigens likely follows the release of NETs and associated 
PADs. Autoantibodies to citrullinated histones arise in RA, systemic lupus 
erythematosus, and Felty's syndrome patients. The citrullination of linker 
histone H1 may play a key role in NET release because the H1 histone regulates 
the entry and exit of DNA from the nucleosome. Juxtaposition of citrullinated 
histones with infectious pathogens and complement and immune complexes may 
compromise tolerance of nuclear autoantigens and promote autoimmunity.