Highlights • HLH comprises a broad spectrum of disorders that all present with a cytokine storm. • Diverse animal models of HLH have enhanced our understanding of this disease. • Models of primary ...HLH appoint a major role for IFN-γ in disease pathogenesis. • TNF-α, IL-6, IL-10 and IL-18 are also cytokines of interest in design of treatments. • Targeting hyperactive T cells or DCs may represent an alternative therapeutic option.
Summary
The cytokine storm syndrome ‘haemophagocytic lymphohistiocytosis’ (HLH) is an under‐recognized hyperinflammatory disorder, causing high morbidity and mortality risk in children and adults. It ...can be subdivided into a primary, genetic form and a secondary, acquired form that complicates diverse infections, malignancies and autoimmune or autoinflammatory disorders. Both subtypes present with the same spectrum of non‐specific symptoms, making accurate diagnosis and rapid treatment initiation challenging. In the last decade, increased awareness and international collaborative efforts fuelled a marked progress in diagnostic protocols and novel treatment strategies for HLH and new diagnostic guidelines are being tailored to specific secondary HLH subtypes. Therapy is gradually shifting its focus from overall immunosuppression towards targeting specific cytokines, cell types or signalling pathways underlying pathophysiology. Nevertheless, continued research efforts remain indispensable to customize therapy to individual patient needs.
Summary
Haemophagocytic lymphohistiocytosis (HLH) comprises a heterogeneous spectrum of hyperinflammatory conditions that are inherited (primary HLH) or acquired in a context of infections, ...malignancies or autoimmune/autoinflammatory disorders (secondary HLH). Genetic defects in the cytotoxic machinery of natural killer and CD8+ T cells underlie primary HLH, with residual cytotoxicity determining disease severity. Improved sequencing techniques have expanded the range of causal mutations and have redefined many cases of secondary HLH as primary HLH and vice versa, blurring the distinction between both subtypes. These insights allow HLH to be conceptualized as a threshold disease, in which interplay between various genetic and environmental factors causes progressive inflammation into a critical point, beyond which uncontrolled activation of immune cells and excessive cytokine production give rise to the cardinal symptoms of HLH. Various pathogenic pathways may thus converge to a common end stage of fulminant HLH.
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.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory syndrome, characterized by the uncontrolled activation of macrophages and T cells, eliciting key symptoms such as ...persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, hyperferritinemia, and coagulopathy. Viral infections are frequently implicated in the onset of active HLH episodes, both in primary, genetic HLH as in the secondary, acquired form. Infections with herpesviruses such as Epstein-Barr virus and cytomegalovirus are the most common. In autoimmune diseases, a link between viral infections and autoreactive immune responses has been recognized for a considerable time. However, the mechanisms by which viruses contribute to HLH pathogenesis remain to be clarified. In this viewpoint, different factors that may come into play are discussed. Viruses, particularly larger DNA viruses such as herpesviruses, are potent modulators of the immune response. By evading immune recognition, interfering with cytokine balances and inhibiting apoptotic pathways, viruses may increase the host's susceptibility to HLH development. In particular cases, a direct connection between the viral infection and inhibition of natural killer cell or T cell cytotoxicity was reported, indicating that viruses may create immunological deficiencies reminiscent of primary HLH.
Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.
We randomly assigned 112 ...children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.
At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology ACR core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 85% vs. 9 of 37 24%, P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.
Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
Mice deficient in IFN-γ (IFN-γ knockout KO mice) develop a systemic inflammatory syndrome in response to CFA, in contrast to CFA-challenged wild-type (WT) mice who only develop a mild inflammation. ...Symptoms in CFA-challenged IFN-γ KO resemble systemic juvenile idiopathic arthritis (sJIA), a childhood immune disorder of unknown cause. Dysregulation of innate immune cells is considered to be important in the disease pathogenesis. In this study, we used this murine model to investigate the role of NK cells in the pathogenesis of sJIA. NK cells of CFA-challenged IFN-γ KO mice displayed an aberrant balance of activating and inhibitory NK cell receptors, lower expression of cytotoxic proteins, and a defective NK cell cytotoxicity. Depletion of NK cells (via anti-IL-2Rβ and anti-Asialo-GM1 Abs) or blockade of the NK cell activating receptor NKG2D in CFA-challenged WT mice resulted in increased severity of systemic inflammation and appearance of sJIA-like symptoms. NK cells of CFA-challenged IFN-γ KO mice and from anti-NKG2D-treated mice showed defective degranulation capacities toward autologous activated immune cells, predominantly monocytes. This is in line with the increased numbers of activated inflammatory monocytes in these mice which was particularly reflected in the expression of CCR2, a chemokine receptor, and in the expression of Rae-1, a ligand for NKG2D. In conclusion, NK cells are defective in a mouse model of sJIA and impede disease development in CFA-challenged WT mice. Our findings point toward a regulatory role for NK cells in CFA-induced systemic inflammation via a NKG2D-dependent control of activated immune cells.
Abstract Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory childhood disorder, characterized by a specific pattern of systemic features and a typical cytokine profile. Patients ...are at risk to develop macrophage activation syndrome (MAS), an acute life-threatening condition defined by excessive proliferation and activation of macrophages and T cells. Defects of unknown cause in the natural killer (NK) cell cytotoxic capacity are presumed to underlie the pathogenesis of MAS and have been detected in sJIA patients. Here, we provide an overview of the cytokine profiles in sJIA and related mouse models. We discuss the influence of cytokines on NK cell function, and hypothesize that NK cell dysfunction in sJIA is caused by altered cytokine profiles.
: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. ...In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.
Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision ...shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, the
production of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease,
systemic juvenile idiopathic arthritis.
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