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.

Natural Killer Cell Dysfunction and Its Role in COVID-19

“…HLH can be either genetic (familial or immunodeficiency syndrome) or acquired, the latter being associated with viral infection, malignancies and autoimmune disease [ 30 ]. The most prominent immunological feature of patients with genetic or acquired HLH is the loss of natural killer (NK) cell effector functions [ 52 , 53 , 54 ]. Familial hemophagocytic lymphohistiocytis (FHL) is an autosomal recessive disease caused by several gene mutations that participate in the granule-dependent cytotoxic function of NK and T cells [ 55 ].…”

Pathogen Infection Recovery Probability (PIRP) Versus Proinflammatory Anti-Pathogen Species (PIAPS) Levels: Modelling and Therapeutic Strategies

“…However, in certain immunodysfunction disorders, particularly certain hyperinflammatory disorders, such as in cytokine release syndromes (CRS) or cytokine storm (CS) [4][5][6][7][8][9][10][11][12] , macrophage activation syndromes (MAS) or macrophage-cytokine selfamplifying loop (MCSAL) 11 , WBS proliferative disorders 4 , certain PIAPS (e.g., Interleukin-6 or IL-6) can grow out of control or not being efficiently dampened (blue dashed line in Fig. 1) by the host anti-inflammatory species (e.g., IL-10) even after te where the pathogen level may be very low or have been cleared.…”

“…The pathogens here mainly include but may not be limited to, bacteria, viruses (such as the new SARS-cov-2 virus causing the covid-19 pandemic), or certain other species that can trigger or initiate a host immune system responses resulting in the production (clonal expansion) of anti-pathogen species (APS), particularly a series of proinflammatory antipathogen species (PIAPS). PIAPS here mainly refer to "double-edged sword" species such as certain white blood cells (wbcs) or their generated/related species, such as oxidative radical species and antibodies [4][5][6] , cytokines [7][8][9][10][11][12][18][19][20] , etc. "Doubleedged sword" refers to certain PIAPS that not only attack the pathogens but also attack host normal cells and tissues [4][5][6][7][8][9][10][11][12][18][19][20] .…”

Pathogen Infection Recovery Probability (PIRP) Versus Proinflammatory Anti-Pathogen Species (PIAPS) Levels: Modelling and Therapeutic Strategies

“…Certain APS (such as certain pathogen specific antibodies) are expected to remain at their equilibrium levels for certain period of time so the same pathogen infection can be prevented or inhibited (principle of vaccination), though antibody equilibrium level slow decay in long period of time are normal or expected [13][14][15][16][17]. However, in certain immunodysfunction disorders, particularly certain hyperinflammatory disorders, such as cytokine release syndromes (CRS) or cytokine storm (CS) [4][5][6][7][8][9][10][11][12], macrophage activation syndromes (MAS) or macrophage-cytokine self-amplifying loop (MCSAL) [11], WBS proliferative disorders [4], certain PIAPS can grow out of control or not being efficiently dampened by the host anti-inflammatory species (e.g., IL-10) even after te where the pathogen may have been eliminated. It has been known that a number of PIAPS attack or damage normal or healthy cells resulting in tissue death (gangrene) and multiple organ dysfunctions or failures [2,[4][5][6][7][8][9][10][11][12][18][19][20].…”

“…Based on this model, the PIRP-PIAPS curve are divided into two stages: 1) Stage I or the PIRP rising stage corresponds to pathogen/APS evolution time period between t0 to te as shown in Figure 1: The PIRP of the pathogen infected host starts to rise as the host normal immune response generated APS (including PIAPS) are growing efficiently from initial levels of x0 (x0 can be zero for pathogen specific APS) and eventually approaching and maintaining at their equilibrium levels xe (blue solid line) where the pathogens are being eliminated or cleared. 2) Stage II or the PIRP descending stage: The PIAPS level further grow beyond their equilibrium levels xe as represented by the long dashed blue line (representing immunodysregulation such as hyperinflammatory disorders) [2,[4][5][6][7][8][9][10][11][12][18][19][20], the PIRP descends presumably due to excessive PIAPS start to damage the normal or healthy tissues or organs. Eventually the PIRP could descend to a very low level due to heavy damages of tissues (particularly lung tissues) that could result in multiple organ failures [2,[7][8][9][10][11][12][18][19][20].…”