Transient natural killer cell dysfunction associated with interleukin‐18 overproduction in systemic juvenile idiopathic arthritis

Takakura, Maiko; Shimizu, Masaki; Yakoyama, Tadafumi; Mizuta, Mao; Yachie, Akihiro

doi:10.1111/ped.13679

Cited by 16 publications

(15 citation statements)

References 5 publications

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“…This effect is mainly thought to be driven by the excessive levels of IL-18 found in patients with sJIA. Although IL-18 is a stimulatory cytokine for cytotoxicity and cytokine production by NK cells, it failed to induce a cytotoxic response, an increased perforin expression and degranulation by NK cells (121,153). More surprisingly, stimulation with IL-18 did not elicit production of IFN-γ by sJIA NK cells, which was caused by a reduced phosphorylation downstream of the IL-18 receptor β (121,125).…”

Section: Nk Cell Dysfunction In Sjiamentioning

confidence: 98%

Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome

2020

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Natural killer (NK) cells are innate immune lymphocytes with potent cytolytic and immune-regulatory activities. NK cells are well-known for their ability to kill infected and malignant cells in a fast and non-specific way without prior sensitization. For this purpose, NK cells are equipped with a set of cytotoxic molecules such as perforin and apoptosis-inducing proteins. NK cells also have the capacity to produce large amounts of cytokines and chemokines that synergize with their cytotoxic function and that ensure interaction with other immune cells. A less known feature of NK cells is their capacity to kill non-infected autologous cells, such as immature dendritic cells and activated T cells and monocytes. Via the release of large amounts of TNF-α and IFN-γ, NK cells may contribute to disease pathology. Conversely they may exert a regulatory role through secretion of immuno-regulatory cytokines such as GM-CSF, IL-13, and IL-10. Thus, NK cells may be important target and effector cells in the pathogenesis of autoinflammatory diseases, in particular in those disorders associated with a cytokine storm or in conditions where immune cells are highly activated. Key examples of such diseases are systemic juvenile idiopathic arthritis (sJIA) and its well-associated complication, macrophage activation syndrome (MAS). sJIA is a chronic childhood immune disorder of unknown etiology, characterized by arthritis and systemic inflammation, including a daily spiking fever and evanescent rash. MAS is a potentially fatal complication of autoimmune and autoinflammatory diseases, and most prevalently associated with sJIA. MAS is considered as a subtype of hemophagocytic lymphohistiocytosis (HLH), a systemic hyperinflammatory disorder characterized by defective cytotoxic pathways of cytotoxic T and NK cells. In this review, we describe the established features of NK cells and provide the results of a literature survey on the reported NK cell abnormalities in monogenic and multifactorial autoinflammatory disorders. Finally, we discuss the role of NK cells in the pathogenesis of sJIA and MAS.

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Section: Nk Cell Dysfunction In Sjiamentioning

confidence: 98%

Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome

2020

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“…NK cell dysfunction causing hypercytokinemia and hyperinflammation. However, it is known that cytokines can drive NK cell differentiation and induce NK cell dysfunction (37–39). Also, macrophage dysfunction is known in FA cells (40–42) and cytokines secreted by macrophages have been reported to inhibit NK cell function (43).…”

Section: Discussionmentioning

confidence: 99%

Natural Killer Cell Degranulation Defect: A Cause for Impaired NK-Cell Cytotoxicity and Hyperinflammation in Fanconi Anemia Patients

et al. 2019

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Fanconi anemia (FA) is a rare inherited syndrome characterized by progressive bone marrow failure (BMF), abnormal skin pigmentation, short stature, and increased cancer risk. BMF in FA is multifactorial and largely results from the death of hematopoietic stem cells due to genomic instability. Also, inflammatory pathology in FA has been previously reported, however the mechanism is still not clear. In literature, decreased NK-cell count and/or impaired NK-cell activity, along with other immunological abnormalities have been described in FA-patients ( 1 ). However, to the best of our knowledge, this is the first report showing a defective degranulation mechanism leading to abnormal NK-cell cytotoxicity in FA-patients, which may explain the development of a hyperinflammatory response in these patients. This may predispose some patients to develop Hemophagocytic lymphohistiocytosis (HLH) which manifests with prolonged fever, progressive cytopenias and organomegaly. Early diagnosis and initiation of immunosuppressive therapy in these patients will help to better manage these patients. We also propose FA genes to be listed as a cause of familial HLH.

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“…Previous studies have reported that NK-cell dysfunction and a decreased number of cells were found in s-JIA [16, [21][22][23]. A previous report has shown that exposure to high concentrations of IL-18 can induce NK-cell death [21][22][23]. Furthermore, de Jager et al have reported that impaired NK-cell function in s-JIA involves a defect in the IL-18 receptor b phosphorylation [22].…”

Section: Acquired Nk-cell Dysfunction and Il-6 And Il-18 Overproduction In S-jiamentioning

confidence: 99%

“…Reduced NK cytotoxic activity is associated with heterozygous mutations in causative genes for pHLH in some patients [13,18]. Moreover, in vivo exposure to highly elevated IL-6 and IL-18 might induce NK-cell dysfunction and their decrease, respectively [19][20][21][22][23].…”

Section: Pathogenesis Of Masmentioning

confidence: 99%

Macrophage activation syndrome in systemic juvenile idiopathic arthritis

Shimizu

2021

Immunological Medicine

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Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of systemic juvenile idiopathic arthritis (s-JIA). An immunological feature is the excessive activation and proliferation of T lymphocytes and macrophages. Massive hypercytokinemia is strongly associated with its pathogenesis, particularly the overproduction of interleukin (IL)-1, IL-6 and IL-18; interferon (IFN)-c; and tumor necrosis factor (TNF)-a. Furthermore, heterozygous mutations in causative genes for primary hemophagocytic lymphohistiocytosis and in vivo exposure to highly elevated levels of IL-6 and IL-18 might induce natural killer cell dysfunction and decrease their numbers, respectively. A proper diagnosis is important to begin appropriate therapeutic interventions and change an unfavorable prognosis. The 2016 ACR/EULAR classification criteria for MAS have a high diagnostic performance; however, the diagnostic sensitivity for onset is relatively low. Therefore, careful monitoring of laboratory values during the course of MAS is necessary to diagnose it early in s-JIA. Further studies on the diagnosis and monitoring of disease activity using serum cytokine profile and a targeted cytokine strategy are required.

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Transient natural killer cell dysfunction associated with interleukin‐18 overproduction in systemic juvenile idiopathic arthritis

Cited by 16 publications

References 5 publications

Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome

Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome

Natural Killer Cell Degranulation Defect: A Cause for Impaired NK-Cell Cytotoxicity and Hyperinflammation in Fanconi Anemia Patients

Macrophage activation syndrome in systemic juvenile idiopathic arthritis

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