micrornas targeting programmed cell death protein 1 (pd-1) promote natural killer cell exhaustion in rheumatoid arthritis

Natural killer (nk) cells play a role in the pathogenesis of rheumatoid arthritis (ra). upregulated levels of programmed cell death protein 1 (pd-1) is a sign of exhausted nk cells that could be regulated by micrornas (mirnas). in this investigation, we determined pd-1 expression on nk cells (as a representation of nk cell exhaustion) in ra patients and evaluated if mirnas are involved in the modulation of pd-1 expression in nk cells. peripheral blood specimens were obtained from 40 ra patients and 20 healthy subjects. nk cells were isolated by negative selection from a pool of peripheral blood mononuclear cells. the frequency of pd-1–expressing nk cells and the expression of pd-1 on nk cells were analyzed by flow cytometry. real-time pcr was used to measure the expression levels of pd-1 mrna and mirnas in the nk cells. the percentage of the pd-1–expressing nk cells and mean fluorescence intensity (mfi) of pd-1 expression on the nk cells were significantly higher in the ra cases compared to the controls. the mrna expression of pd-1 was significantly upregulated in nk cells from ra patients compared to healthy subjects. the expression levels of mir-28, mir-138, and mir-4717 were significantly downregulated in the nk cells from ra patients compared to the healthy group. in ra, mirnas probably regulate the nk cell exhaustion process through driving pd-1 expression.