Inflammatory Gene Expression Profile and Defective Interferon‐γ and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients

Abstract

Objective. Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA.Methods. Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age-matched healthy controls. Cytokines (NK cellstimulating and others) were quantified in plasma samples (n 5 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n 5 10), together with their interferon-g (IFNg)-producing function (n 5 8).Results. NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune-regulating genes such as IL10RA and GZMK. In the patients' plasma, interleukin-18 (IL-18) levels were increased, and a decreased ratio of IFNg to IL-18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin-like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56 bright NK cells and defective IL-18-induced IFNg production and signaling were demonstrated.Conclusion. NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK-related pathways, such as granzyme K expression and IL-18-driven IFNg production, may contribute to the immunoinflammatory dysregulation in this disease.Systemic juvenile idiopathic arthritis (JIA) is a chronic immunoinflammatory childhood disorder of unknown etiology that is characterized by arthritis and systemic features such as quotidian fever, rash, lymphadenopathy, and serositis (1,2). An interplay of environmental factors and genetic predisposition is considered to underlie the pathogenesis (1). About 10% of systemic JIA patients develop

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“…This possibility is supported by Bracaglia et al who demonstrate a strong connection between levels of IFNγ and IFNγ-induced chemokines in SJIA patients with MAS, but not with active sJIA alone (49). However, IL-18-driven IFNγ production cannot be the only determinant in driving MAS, as some patients with active SJIA without features of MAS have high levels of IL-18 without increased levels of IFNγ (48–52), and patients with lupus-associated MAS do not have markedly elevated IL-18 levels (53). To reconcile these contradictory data, Put et al describe defective IL-18-induced IFNγ production and defective IL-18 signaling in NK cells isolated from patients with SJIA without evidence of MAS (52).…”

“…However, IL-18-driven IFNγ production cannot be the only determinant in driving MAS, as some patients with active SJIA without features of MAS have high levels of IL-18 without increased levels of IFNγ (48–52), and patients with lupus-associated MAS do not have markedly elevated IL-18 levels (53). To reconcile these contradictory data, Put et al describe defective IL-18-induced IFNγ production and defective IL-18 signaling in NK cells isolated from patients with SJIA without evidence of MAS (52). These data suggest that SJIA patients may be protected from the development of MAS by defective IL-18 signaling in lymphocytes, which would explain how high levels of IL-18 in some patients with active SJIA are not driving aberrant IFNγ production and MAS.…”

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“…Nonetheless, such findings represent only ∼35% of patients with systemic JIA–MAS, indicating that the majority do not have alterations in genes known to be associated with FHLH. Although this percentage may in fact be shown to be higher as additional genes are identified and noncoding mutations are accounted for, recent data call into question whether there is any defect at all in natural killer cell cytotoxic function in systemic JIA .…”

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“…Several studies suggest a role for natural killer (NK) cells, part of the innate immune system, in sJIA, particularly during MAS 19– 24 . In the most recent study, analysis of RNA sequencing data from sJIA NK cells revealed an enrichment of inflammatory pathways with downregulation of IL-10 receptor A and granzyme K 23 .…”