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

Abstract

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.

Keywords: MAS; autoinflammation; immune-regulation; natural killer cell; sJIA.

Figure 1

NK cell subtypes and receptor-ligand interaction between NK cell and target cell. (A) CD56^bright and CD56^dim NK cells, primarily found in the peripheral blood, with a selection of characteristic markers. (B) Tissue-resident NK cells from the liver, lung, and uterus express overlapping markers with peripheral NK cells. Each tissue-specific NK cell subtype displays a characteristic phenotype which allows differentiation from peripheral NK cells. (C) Selection of NK cell receptors and their corresponding ligands on target cells. Inhibitory receptors are in blue, activating receptors are in green and receptors with dual function are in gray. The balance of inhibitory and activating signals define the activity or tolerance of NK cells. Activated NK cells will release cytotoxic proteins and cytokines to eliminate the target cells. KIR, killer-immunoglobulin receptor; HLA, human leukocyte antigen; KLRG1, killer cell lectin-like receptor G1; ULBP, UL16 binding protein; Rae, Retinoic acid early inducible; MIC, MHC class I polypeptide-related sequence.