NK cells dysfunction in systemic lupus erythematosus: relation to disease activity

Abstract

Through their cytotoxic capacities and cytokine production, natural killer (NK) cells modulate autoimmune diseases. However, their role in the pathogenesis of systemic lupus erythematosus (SLE) has not been extensively studied. The aim of this study was to analyse the immunophenotypic and functional characteristics of the two major NK cell subsets in SLE and relate them with disease activity. Peripheral blood samples from 44 patients with active (n = 18) and inactive SLE (n = 26) and 30 controls were analysed by flow cytometry to evaluate NK cell subsets, according to: the differential expression of CXCR3 and CD57; expression of granzyme B and perforin; and production of interferon gamma (IFN-γ) and tumor necrosis alpha (TNF-α), after PMA/ionomycin activation. A clear decrease in absolute and relative numbers of circulating NK cells was found in SLE, particularly in active disease, while the proportions of the major NK cell subsets were unaffected. Active SLE was associated with a reduced CXCR3 expression on both NK cell subsets and a lower frequency of CD56(dim) NK cells expressing CXCR3. Furthermore, granzyme B expression was decreased in both SLE groups, but the percentage of NK cells expressing granzyme B and perforin was higher, particularly in active disease. We found a significant decrease in the percentage of CD56(bright) and CD56(dim) NK cells producing TNF-α and of its expression on CD56(dim) NK cells in active disease, while IFN-γ expression on CD56(bright) NK cells was increased in both SLE groups. Our findings suggest that NK cell subsets exhibit unique phenotypic and functional changes that are particularly evident in active SLE, and they may have the potential to affect the disease outcome.

Effect of Interleukin-15 on CD11b, CD54, and CD62L Expression on Natural Killer Cell and Natural Killer T-Like Cells in Systemic Lupus Erythematosus

“…In agreement with the previous studies [31, 32], we found that the percentages of NK cells and NKT-like cells are decreased in PBMC from SLE patients compared to controls. However, The percentages of T cells were comparable to controls.…”

Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus

“…The interpretation that NK cells in PBMCs are depleted as a result of death, therefore, might be partially flawed, as it could also be a result of NK cell migration to target organs in SLE. NK cell trafficking to SLE target sites could explain the reduction in the percentage of CXCR3-positive NK cells in PBMCs of patients with active disease [65], in line with our data from murine models. As CXCR3 has a role in NK cell trafficking to inflamed organs, this reduction in mature CD56 dim CXCR3-positive cells could, in fact, reflect a shift of these cells from the periphery to target organs.…”

“…CD27 High , CD11b Low , CD56 bright immature NK cells have reduced cytotoxic function but increased IFN-g secretion; these cells might be the predominant phenotype in SLE patient PBMCs [49,57,65].…”

IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice

“…Roquin san/san mice display decreased IFN-γ mRNA decay leading to chronic circulating levels of IFN-γ and a lupus-like phenotype [2] and offspring from lupus-prone MRL/lpr mice crossed with IFN-gamma −/− mice have reduced autoantibody titers and less severe end-organ disease [3]. In humans, IFNG gene polymorphisms have been identified in SLE cohorts [4,5] and dysregulated NK cells, T cells, and PBMCs from SLE patients produce elevated amounts of IFN-γ that correlate with SLE Disease Activity Index Scores [6-8]. Mechanistically, IFN-γ induces B cell activating factor (BAFF), a protein critical for B cell differentiation, proliferation, and survival that has been identified as a therapeutic target in SLE [4,9].…”