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.