Rheumatoid arthritis (RA) is now clearly a true
autoimmune disease with accumulating evidence of pathogenic disease-specific autoimmunity to citrullinated
proteins. Citrullination, also termed deimination, is a modification of
arginine side chains catalyzed by
peptidylarginine deiminase (PAD)
enzymes. This post-translational modification has the potential to alter the structure, antigenicity, and function of
proteins. In RA,
antibodies to cyclic citrullinated
peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated
antigens, as whole
proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated
antigens,
fibrinogen,
vimentin,
collagen type II, and
alpha-enolase, are now well established, with others awaiting further characterization. All four
proteins are expressed in the joint, and there is evidence that
antibodies to citrullinated
fibrinogen and
collagen type II mediate
inflammation by the formation of
immune complexes, both in humans and animal models.
Antibodies to citrullinated
proteins are associated with HLA 'shared
epitope' alleles, and autoimmunity to at least one antigenic sequence, the CEP-1
peptide from citrullinated
alpha-enolase (KIHAcitEIFDScitGNPTVE), shows a specific association with
HLA-DRB1*0401, *0404, 620W PTPN22, and smoking.
Periodontitis, in which Porphyromonas gingivalis is a major pathogenic bacterium, has been linked to RA in epidemiological studies and also shares similar gene/environment associations. This is also the only bacterium identified that expresses endogenous citrullinated
proteins and its own bacterial PAD
enzyme, though the precise molecular mechanisms of bacterial citrullination have yet to be explored. Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA.