Figure 8 .

Model for synovial PAD infiltration. Many leucocytes infiltrate the inflamed synovium in RA. When monocytes from the PB enter the synovium, they will differentiate into macrophages. This differentiation process has several consequences for PAD expression: the mRNA expression of PAD4 is lost during differentiation, but the PAD4 protein levels remain unchanged, indicating that the enzyme is not rapidly degraded. For PAD2, the situation is different: the mRNA levels remain more or less the same, but the mRNA is only translated into PAD2 protein in the macrophages. The patterns of PAD expression are identical in patients with RA and healthy controls, but because of the large numbers of macrophages that can be found in the RA (and not in healthy) synovium, the amount of PAD enzyme in the RA synovium will be much higher than in healthy synovium. During apoptosis or necrosis of the PAD-containing macrophages, free intracellular Ca²⁺ levels are increased, resulting in activation of the PAD enzymes and citrullination of cellular proteins. In the macrophages, vimentin is specifically citrullinated after increase of cytoplasmic Ca²⁺. Furthermore, PAD enzymes may leak out of necrotic cells, causing the citrullination of extracellular proteins (for example, fibrin²¹).