Natural killer T cell deficiency in active adult‐onset Still's disease: Correlation of deficiency of natural killer T cells with dysfunction of natural killer cells

Abstract

Objective. To examine the levels and functions of natural killer (NK) and natural killer T (NKT) cells, investigate relationships between NK and NKT cells, and determine the clinical relevance of NKT cell levels in patients with adult-onset Still's disease (AOSD).Methods. Patients with active untreated AOSD (n ‫؍‬ 20) and age-and sex-matched healthy controls (n ‫؍‬ 20) were studied. NK and NKT cell levels were measured by flow cytometry. Peripheral blood mononuclear cells were cultured in vitro with ␣-galactosylceramide (␣GalCer). NK cytotoxicity against K562 cells and proliferation indices of NKT cells were estimated by flow cytometry.Results. Percentages and absolute numbers of NKT cells were significantly lower in the peripheral blood of AOSD patients than in that of healthy controls. Proliferative responses of NKT cells to ␣GalCer were also lower in patients, and this was found to be due to proinflammatory cytokines and NKT cell apoptosis. In addition, NK cytotoxicity was found to be significantly lower in patients than in healthy controls, but NK cell levels were comparable in the 2 groups. Notably, this NKT cell deficiency was found to be correlated with NK cell dysfunction and to reflect active disease status. Furthermore, ␣GalCer-mediated NK cytotoxicity, showing the interaction between NK and NKT cells, was significantly lower in AOSD patients than in healthy controls.Conclusion. These findings demonstrate that NK and NKT cell functions are defective in AOSD patients and suggest that these abnormalities contribute to innate immune dysfunction in AOSD.

Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis

“…Previous reports described reduced NK cell function in patients with s-JIA and AOSD [30][31][32][33]. The mechanism underlying impaired NK cell function in patients with s-JIA has been associated with a defect in IL-18 receptor β phosphorylation [34].…”

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

“…MAIT cells and NKT cells were identified phenotypically as CD3 + TCRgd 2 Va7.2 + CD161 high and CD3 + 6B11 + cells, respectively, by flow cytometry as previously described (4,5,17,19). To confirm whether the reported proportions of MAIT cells in PBMCs contain the MAIT cell rearrangement, we performed TCR genotyping in sorted CD3 + TCRgd 2 Va7.2 + CD161 high cells.…”

“…IFN-g, IL-17, and IL-4 expression in MAIT cells were detected by intracellular cytokine flow cytometry as previously described (3,4,19,26,31). In brief, freshly isolated PBMCs (1 3 10 6 /well) were incubated in 1 ml complete media, consisting of RPMI 1640, 2 mM L-glutamine, 100 U/ml penicillin, and 100 mg/ml streptomycin, and supplemented with 10% FBS (Life Technologies BRL, Grand Island, NY) with or without ERK (PD98059, 50 mM; Calbiochem, San Diego, CA) for 1 h, p38 MAPK (SB220025, 10 mM; Calbiochem) for 1 h, or calcineurin (cyclosporin A [CsA], 2 mM; Calbiochem) inhibitors for 30 min.…”

“…Therefore, NKT cells have been implicated in the control of autoimmune diseases, cancer, and infectious diseases (16). Our previous studies and those by other groups have demonstrated numerical and functional deficiencies of NKT cells in autoimmune diseases (17)(18)(19)(20). Although MAIT and NKT cells exclusively share the expression of the transcription factor PZLF (ZBTB16), emphasizing a close lineage relationship between these two distinct subsets, MAIT cell ontogeny is clearly different from NKT cells (5,21,22).…”

What rheumatologists need to know about innate lymphocytes

“…NK cytotoxicity was found to be significantly lower in patients specifically with adult-onset Still's disease than in healthy controls, but NK cell levels were comparable 56 . This appeared to be related to iNKT cells (see below).…”