Figure 1

Schematic representation of the processes that may lead to the citrullination of proteins (left panel) and the immune response to these proteins (right panel). As discussed in the text (under the headings 'When does citrullination occur?' and 'Which citrullinated proteins are likely to be found in the RA synovium?'), peptidylarginine deiminase (PAD)-containing inflammatory cells infiltrate the site of inflammation. At the onset of death of these cells, the intracellular calcium concentration is raised, thereby causing activation of PAD enzymes and consequently citrullination of proteins. This process is not specific for rheumatoid arthritis (RA; see section entitled 'Is the occurrence of synovial citrullinated proteins a phenomenon specific to RA?'). A combination of impaired clearance of dying cells [42], presence of 'danger signals' [41] and genetic factors may blend into a susceptible environment in which the presence of citrullinated proteins leads to an immune response (see section entitled 'Why are anti-citrullinated protein antibodies so specific for RA?'). As the result of this RA-specific immune response, RA-specific anti-CCP (cyclic citrullinated peptide) antibodies are produced.