Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis

The etiology of rheumatoid arthritis (RA) is thought to involve dysfunction of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway; PD-1 negatively regulates autoimmunity by interacting with its ligand, PD-L1. We therefore investigated PD-1/PD-L1 expression in synovial tissue of patients with RA. We immunohistochemically stained synovial specimens from 51 patients with RA and assessed the association between PD-1/PD-L1 expression and rheumatoid factor (RF), the total count of infiltrating T cells, C-reactive protein (CRP), and Krenn's synovitis score. PD-1 expression on infiltrating lymphocytes was detected in 34/51 RA cases (66.7%), while PD-1 expression was very mildly correlated only with the number of total infiltrating T cells (R-2=0.1011, P=0.0230). On the other hand, PD-L1 expression on synovial lining cells was observed in 37/51 RA cases (72.5%). Furthermore, a higher PD-L1 expression was significantly associated with RF positive state (P=0.0454), and the correlations between PD-L1 expression and the number of infiltrating T cells (R-2=0.5571, P<0.0001), CRP (R-2=0.4060, P<0.0001), and Krenn's synovitis score (R-2=0.7785, P<0.0001) were confirmed. PD-1 was expressed on infiltrating lymphocytes, while PD-L1 was expressed on synovial lining cells; the expression of PD-L1 on synovial lining cells was significantly correlated with the active state of the disease. These data suggest that PD-1/PD-L1 pathway may have an important role in the pathogenesis of RA.