Abstract
Natural killer (NK) cells may play an important role in the pathogenesis of SLE. Interleukin(IL)-15, an NK-enhancing cytokine, is over-expressed in SLE patients. In the present study, we examined the effect of IL-15 on NK cytotoxicity of SLE patients, and the expression of various activating and inhibitory NK receptors on NK cells from SLE patients in relation to disease activity. We also sought to determine how IL-15 would affect the NK receptor expression on NK cells from SLE patients. PBMCs were collected from 88 SLE patients with inactive disease activity (SLEDAI score<6) and active disease activity (SLEDAI score≥6), 26 age-matched healthy adults were used as controls. PBMC were incubated in the presence or absence of IL-15 (10ng/ml) for eighteen hours. CD3-CD56+ lymphoctes were gated using flow cytometry and further divided into CD56dim and CD56bright subsets according to the MFI of CD56. We observed that 1. Serum IL-15 was elevated in SLE patients, and higher in active disease than in inactive disease; 2. NK cytotoxicity of SLE patients was deficient compared to controls and showed an impaired response to IL-15 compared to controls; 3.CD69, CD94, NKG2A, NKp30, and CD158b on NK cells from SLE patients were higher than controls, and could be further enhanced by IL-15; 4. NKp46 expression from SLE patients was higher than controls, but down-regulated by IL-15; 5.Deficient NKG2D and NKAT-2 expression were found on NK cells from SLE patients, which were enhanced by IL-15; 6. A unique NKp46- subset and CD158b+ subsets were observed in NK cells from SLE patients but not controls. 7. Unlike controls, CD158k on NK cells from SLE patients failed to respond to IL-15. Taken together, we demonstrated the aberrant NCR and iNKR expression on NK cells and their distinct response to IL-15 in SLE patients. As IL-15 predominantly aggravates the aberrant NKR expression found in SLE, IL-15 antagonist may have therapeutic benefits in SLE patients.
Highlights
Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease with a wide array of clinical manifestations characterized by the presence of high titers of autoantibodies, elevated circulating immune complexes, and complement deficiency [1, 2]
Our finding is consistent with Zhu et al who recently showed that the serum level of IL-15 was significantly elevated in SLE patients and correlated with their mRNA expression [30]
The percentages of Natural killer (NK) cells are decreased in PBMC from SLE patients compared to controls
Summary
Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease with a wide array of clinical manifestations characterized by the presence of high titers of autoantibodies, elevated circulating immune complexes, and complement deficiency [1, 2]. The etiology and pathogenesis of SLE remained to be elucidated. Previous studies a have found a decrease in NK cell numbers, impaired NK cytotoxicity and defects of NK differentiation in SLE patients [7,8,9]. NK cells can serve as a double-edge sword as it may promote the inflammation in SLE by producing interferon-gamma (IFN-γ) which may promote B cell activation and aut0-antibody production [10]. NK cells may ameliorate the inflammation by their ability to kill activated T cells and macrophages. The relationship between NK cell abnormalities and SLE activity was not clearly established and the role of NK cells in the pathogenesis of SLE remains controversial. We have demonstrated the dysfunctional NK and NKT-like cells in SLE patient with regard to CD11b and CD62L expression [12]
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