Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and joint destruction. previous studies have shown that natural killer (nK) cells may play an important role in the pathogenesis of RA. Interleukin (IL)-15, a pro-inflammatory cytokine which induces proliferation and differentiation of NK cells, is overexpressed in RA. In this present study, we examine various NKRs and adhesion molecule expression on NK cells from RA patients and their response to IL-15 stimulation. We also sought to study cytokine-induced memory-like (CIML) NK cells in RA patients. We established that 1. RA patients had higher NK cell percentages in peripheral blood and their serum IL-15 levels were higher compared to healthy volunteers; 2. NK cells from RA patients showed lower NKp46 expression and an impaired CD69 response to IL-15; 3. NK cells from RA patients showed higher CD158b and CD158e expression but lower CD62L expression; 4. exogenous IL-15 up-regulated CD69, CD158b, CD158e but down-regulated NKp46 and CD62L expression in RA; 5. As to CIML NK cells, restimulation-induced NK cytotoxicity and IFN-γ production was impaired in RA patients, 6. Reduced NKp46, perforin, and granzyme B expression on NK cells was found in RA patients with bone deformity and erosion, 7. RA disease activity (DAS28) showed inverse correlation with the percentages of CD56 + CD3 − NK cells, and NKp46 and perforin expression on NK cells, respectively. Taken together, our study demonstrated differential expression of various NK receptors in RA patients. NKp46, CD158e, and perforin expression on NK cells may serve as markers of RA severity.

Natural killer cells in inflammatory autoimmune diseases

“…In RA, the frequency of NK cells is increased in peripheral blood of patients 81,115 but these NK cells consistently display impaired effector functions such as reduced IFN‐γ production and decreased cytotoxicity 115–118 . This may be due to upregulation of inhibitory receptors such as CD161 117 and NKG2A, 119 or downregulation of activating receptors such as CD16 116 .…”

“…Abundant NK cells are present in RA synovium and most harbour a unique CD56 bright phenotype 25,26,115,122 . RA synovial NK cells are CD69 + NKp44 + , indicative of their activated state, but are perforin low 25,26,115,122 .…”

“…Abundant NK cells are present in RA synovium and most harbour a unique CD56 bright phenotype 25,26,115,122 . RA synovial NK cells are CD69 + NKp44 + , indicative of their activated state, but are perforin low 25,26,115,122 . They also upregulate surface expression of inhibitory CD94‐NKG2A, 123 which strongly inhibits NK cell production of IFN‐γ and TNF and also restrains cytotoxicity upon binding to its ligand, HLA‐E 25,119,122 .…”

“…Unlike circulating NK cells, synovial NK cells have low KIR expression, 25,26,81 but express chemokine receptors, such as CCR5, CXCR3 and CCR1, which may facilitate their preferential recruitment into RA synovium 26,81 . Given the low cytotoxicity and IFN‐γ production of synovial NK cells, 115 these NK cells likely contribute to local joint inflammation by producing other pro‐inflammatory mediators. Reciprocal activation of joint‐infiltrating CD56 bright NK cells and CD14 + inflammatory monocytes has also been suggested in RA 25,124 .…”

COVID-19, rheumatic diseases and immune dysregulation—a perspective

“…Unfortunately, many of the clinically available biomarkers that are reported to be associated with COVID-19 are also abnormal in rheumatic diseases (e.g. NK cell dysfunction, elevated IL-6, CRP, hypocomplementemia), and they do not always parallel the disease activity in these patients [ 72 – 74 ]. Hence, biomarkers that can distinguish rheumatic disease flares from COVID-19 are desperately needed.…”