379 research outputs found
La ville rouge de Michael Matthys : portrait de ville, une logique du fragmentaire
No full textColloque organisé sous la direction de Jean-PierreMontier, David Martens et Sophie Lécole SolnychkineInternational audienceDans son album La ville rouge (2009), Michael Matthys réunit des images de la ville de Charleroi, conçues à partir du relevé cinématographique et de l’empreinte photographique d’espaces-tiers, réalisées avec du sang de bœuf issu des abattoirs de Gilly et suivant les développements d’un dessin d’esquisse. Nous interrogeons les relations entre ces fragments-mondes, attachés à la viscosité du rouge sang, à la versatilité du trait et à une représentation en défaut, et les éclats de réalité d’un milieu urbain identifié comme le « pays noir »
La Ville rouge de Michael Matthys. Portrait de ville, une logique du fragmentaire
No full textOuvrage publié sous la direction de Sophie Lécole Solnychkine, David Martens, Jean-Pierre MontierInternational audienceDans son album La Ville rouge (2009), Michael Matthys réunit des images de la ville de Charleroi, conçues à partir du relevé cinématographique et de l'empreinte photographique d'espaces-tiers, réalisées avec du sang de boeuf issu des abattoirs de Gilly et suivant les développements d'un dessin d'esquisse. Nous interrogeons les relations entre les fragments-mondes, attachés à la viscosité du rouge sang, à la versatilité du trait et à une représentation en défaut, et les éclats de réalité d'un milieu urbain identifié "comme le "pays noir"
sj-docx-1-nah-10.1177_02601060231166821 - Supplemental material for Change in carbohydrate intake one year after Roux-en-Y gastric bypass: A prospective study
No full textSupplemental material, sj-docx-1-nah-10.1177_02601060231166821 for Change in carbohydrate intake one year after Roux-en-Y gastric bypass: A prospective study by Joke Vliebergh, Ina Gesquiere, Veerle Foulon, Patrick Augustijns, Matthias Lannoo, Ellen Deleus, Ann Meulemans, Chantal Mathieu, Ann Mertens, Christophe Matthys, Bart Van der Schueren and Roman Vangoitsenhoven in Nutrition and Health</p
Collageen-geïnduceerde artritis als een diermodel voor reumatoïde artritis: rol van IFN-gamma in immuunmodulatie door mesenchymale stamcellen en in extra-articulaire manifestaties.
No full textOver an extended period of time, work in our laboratory focused on unravelling the role of interferon-γ (IFN-γ) in collagen-induced arthritis (CIA), a well characterised animal model for human rheumatoid arthritis (RA). IFN-γ was found to display anti-inflammatory properties in CIA since IFN-γ receptor knock-out (IFN-γR KO) mice developed CIA more rapidly and with a higher severity as compared to their wild-type counterparts. The protective effect of IFN-γ could be explained by its suppressive effects on neutrophil mobilisation, activation of macrophages/osteoclasts and its role in the activation of regulatory T cells. The dogma that IFN-γ acts as a proinflammatory cytokine was questioned by these findings. Moreover, IFN-γ could be considered a novel therapy for RA, a perception confirmed by numerous clinical trials concerning IFN-γ in RA. In the quest for novel therapies for RA, mesenchymal stem cells (MSCs) have recently been proposed. They are multipotent cells that combine interesting characteristics such as tissue regeneration and immunosuppression and might therefore prove to be ideal therapeutics for RA. Since IFN-γ has been identified as an activator of the immuosuppressive capacities of MSCs, in this thesis we investigated the potential of MSCs to suppress the joint pathology in CIA and the effect of IFN-γ on this suppression. Although the joint pathology in CIA resembles that of RA remarkably well, RA is associated with extra-articular manifestations in for instance lung tissue. In CIA no reports of pulmonary involvement were reported. In this thesis we therefore investigated whether mice with CIA would develop pulmonary manifestations and analysed the role of IFN-γ on this systemic pathology.MSCs were isolated from the bone marrow of wild-type and IFN-γR KO mice and after several passages homogenous populations of MSCs were obtained. By culturing anti-CD3-stimulated T cells in vitro in the presence of MSCs we could demonstrate that T cell responses were suppressed by MSCs in a dose-dependent manner. IFN-γR KO MSCs were less suppressive than wild-type MSCs, indicating an IFN-γ-dependent mechanism was involved in the T cell suppression. By stimulating MSCs with IFN-γ we could demonstrate that the production of programmed death ligand-1, inducible nitric oxide synthase and cyclo-oxygenase-2, but not indoleamine 2,3-dioxygenase was involved in the immunosuppression mediated by MSCs. Despite their potent in vitro suppressive effects, MSCs were unable to counteract in vivo anti-CD3-induced T cell proliferation in mice. MSCs also failed to suppress CIA, even when they were administered at multiple time points or via different routes. This was reflected in unchanged humoral and cellular responses towards collagen type II. Together these data demonstrate that the immunosuppressive potential of MSCs in vitro can not be extrapolated to an in vivo situation.When MSCs are considered as a therapeutic in RA, thorough investigation of the effect of MSCs on all cell types involved in the pathogenesis of RA is necessary. Therefore, we investigated the effect of MSCs on osteoclasts, the cell type responsible for bone degradation in the joints of RA patients. Using mouse embryo fibroblasts (MEFs) as a source of fibroblasts, we developed an in vitro co-culture system between MEFs and splenocytes from mice with CIA. We could demonstrate that MEFs could stimulate the development of osteoclasts from splenocytes even without addition of osteoclast growth factors. When MEFs were substituted by MSCs, no osteoclasts could be detected. Only when receptor activator of nuclear factor-kB ligand (RANKL), a potent osteoclast inducer, was added osteoclasts developed. In the presence of tumor necrosis factor-α (TNF-α), osteoclasts were also not formed. Thus, MSCs can only support osteoclast differentiation when RANKL is present. As a consequence, whether MSCs will induce osteoclast differentiation in the joint of RA patients will probably depend on the cytokine balance present in the joint and administration of these cels in inflammatory conditions (containing RANKL and TNF-α) possibly has detrimental effects.As a second main goal in this thesis, we investigated whether pulmonary manifestations, which regularly complicate RA, were also present in CIA in mice. On macroscopic examination of the lungs 21 days after the induction of CIA, lesions could be detected on the surface of the lungs in IFN-γR KO mice but not in wild-type mice. Elevated numbers of macrophages and neutrophils were detected in bronchoalveolar lavage fluid of IFN-γR KO mice. Upon histological examination of the lungs, perivascular and peribronchial lymphocytic infiltrates as well as subpleural nodular accumulations of neutrophils and histiocytes could be visualised in lungs of arthritic IFN-γR KO mice but not wild-type mice. In IFN-γR KO mice, this pulmonary infiltration was accompanied by elevated mRNA levels of proinflammatory cytokines and chemokines. Upon functional assessment of the lungs, impaired lung function was ascertained which presented as a stiffening of the lungs. Treating the mice with anti-TNF-α therapy resulted in a complete prevention of joint pathology and a partial but significant reduction of the pulmonary complications. These data indicate that extra-articular manifestations in CIA can be provoked in CIA by interfering with one cytokine signaling pathway i.e. IFN-γ.Previous doctoral research in our laboratory demonstrated that upon immunisation with complete Freunds adjuvant (CFA) without the cartilage antigen collagen type II, IFN-γR KO mice develop arthritic symptoms which are identical to the joint pathology observed in CIA. Upon examination of the lungs, we could demonstrate that IFN-γR KO mice with CFA-induced arthritis displayed similar pulmonary pathology as IFN-γR KO mice with CIA. An important component of CFA is heat-killed Mycobacterium butyricum. Since this M. butyricum is the common factor in both arthritis models, we focused our attention to the M. butyricum to find a possible cause of the lung involvement. After fluorescent labelling of the M. butyricum, we could determine that the M. butyricum was present in the lungs of immunised animals. Thus, from these data we can conclude that M. butyricum used for the induction of CIA and CFA-induced arthritis translocates to the lungs after immunisation of IFN-γR KO mice and might locally cause production of proinflammatory cytokines and chemokines, followed by pulmonary inflammation.Summarising our investigations, we can state that although MSCs display potent immunosuppressive potential in vitro, they were unable to counteract in vivo T cell proliferation or CIA. Furthermore, MSCs could, depending on the local cytokine balance, possibly stimulate the development of osteoclasts. These findings are important to keep in mind when considering MSCs as potential therapy for RA. Although CIA is generally considered not to be associated with extra-articular manifestations, we could demonstrate that IFN-γR KO mice with CIA did present with pulmonary pathology. This finding adds relevance to the animal model and offers clear future perspectives both on fundamental and clinical level. We feel that on fundamental level, the model is suited to investigate the association between environmental factors, such as smoking, citrullination in the lungs and the development of arthritis. The fact that these extra-articular manifestations mainly occur in mice that have a mutation in the IFN-γ receptor, might offer new perspectives to the clinic such as treatment of RA patients with IFN-γ, possibly combined with current therapies.status: Publishe
Regulatie van osteoclast differentiatie en functie in muismodellen van artritis
No full textOur laboratory previously demonstrated that IFN-gR KO mice are highly su sceptibility for CIA, an animal model for RA. This increased disease sus ceptibility (as compared to wild-type mice) is accompanied by an increased expansion of CD11b+ cells in the spleen, whi ch is fully ascribed to the use of CFA in the induction procedure. Part of the expanded CD11b+ splenocytes was identified as OCPs, which could d ifferentiate into mature osteoclasts when stimulated with RANKL and M-CS F. These results support the close relationship between the immune and skel etal systems, two overlapping fields that are termed osteoimmunology. The experiments in this thesis were conducted to further unravel the mec hanism of experimental arthritis, focussing on the osteoimmunology field . In the first chapter we considered whether CFA by itself is able to indu ce arthritis. For this purpose, IFN-gR KO and wild-type mice were sensit ised with a single injection of CFA containing heat-killed Mycob acterium butyricum and arthritis was recorded. Symptoms of arthritis appeared in IFN-gR KO but not in wild-type mice and coincided with an expansion of C D11b+ splenocytes. A similar expansion of peripheral CD11b+ cells has be en described in spontaneously developing arthritis in TNF-a transgenic m ice. In our model, bioactive TNF-a was detected in sera of CFA-sensitise d mice, whereas it was undetectable in sera of CFA-injected wild-type mi ce. Splenocytes derived from CFA-sensitised mice spontaneously produced TNF-a and stimulation with Mycobacterium butyricum increased the amount of TNF-a produced per cell. An increased osteoclastogenesis from spleen and blood cells co uld be demonstrated in CFA-challenged mice. Furthermore, stimuli for ost eoclast differentiation (RANKL, OPG and TNF-a) were present in the synov ia of sensitised IFN-gR KO mice, and injection of IFN-gR KO mice with CF A resulted in an increase in the RANKL/OPG ratio. A synergistic effect of TNF-a and RANKL in splenocyte cultures of CFA-chal lenged IFN-gR KO mice compared to naive mice was demonstrated. This synergistic effect of TNF- a with RANKL and the presence of bioactive TNF-a in the circulation of CFA-induced mice, urged us to investigate the efficacy of etanercept, a TNF-a antagonist, in the pathogenesis of this disease. Clinical symptoms remained absent in the etanercept-treated gro up and significantly lower numbers of osteoclasts appeared in the blood leukocyte cultures of the etanercept-treated mice as in those of the CFA -sensitised control mice. Together these data reveal new aspects of CFA in the pathogenesis of CIA. Sensitisation of mice with CFA creates a sit uation in which the deregulation of a single cytokine leads to arthritis by triggering TNF-a driven osteoclastogenesis. In a second chapter we investigated the role of IL-22, a Th17-related cy tokine, in CIA. We first verified whether IL-22 and its specific recepto r (IL-22R1) are expressed in immunised mice. Our data revealed that upon immunisation with CII in Freunds adjuvant, sera of C57Bl/6 mice contai ned high levels of IL-22, and IL-22R1 was expressed in lymphoid tissue, including splenocytes. As to the pathogenesis of CIA, IL-22-/- mice were less susceptible for CIA than wild-type mice, as evident from their dec reased incidence of arthritis and decreased pannus formation. Remarkably , the less severe form of arthritis in IL-22-/- mice was associated with increased CII-specific and total IgG antibody production, whereas cellu lar CII responses were unchanged. In vitro, IL-22 was found to promote o steoclastogenesis, a process that might contribute to its proinflammator y activity in CIA. In conclusion, these data indicate that endogenous IL -22 plays a proinflammatory role in CIA in C57Bl/6 mice. Our data also d emonstrate that IL-22 promotes osteoclastogenesis and regulates antibody production. Since a single transfer of Treg cells improves the clinical outcome of a rthritis without affecting the humoral or cellular immune responses, we investigated in the third part of this doctoral thesis, whether Treg cel ls may interfere with osteoclast differentiation. Osteoclasts were gener ated by stimulation of splenocytes with M-CSF and RANKL and purified Tef f and/or Treg cells were added to the cultures. Treg cells significantly inhibited osteoclast formation. Multiplex flow cytometric analysis reve aled that this inhibition by Treg cells was associated with an increase in the production of osteoclast-inhibiting cytokines, such as GM-CSF, IF N-gamma, IL-5, IL-10, while osteoclast-stimulating cytokines (TNF-a, IL- 1, IL-6 and IL-17), were barely affected or not detectable. Thus, activa ted Treg cells favor the production of osteoclast inhibiting cytokines and improve clinical sympt oms of arthritis. In the last chapter, we investigated the influence of TRAF6 deficiency i n the myeloid cell lineage on the pathogenesis of CIA as well on their o steoclastogenic capacity. Remarkably, TRAF6MC-KO mice were found to be m ore susceptible for CIA as compared to their wild-type littermates. The more severe form of arthritis in TRAF6MC-KO mice was associated with inc reased cellular CII responses, whereas humoral CII responses were unchan ged. Surprisingly, osteoclasts were inducible, and in higher numbers, in cultured splenocytes of immunised TRAF6MC-KO mice than in those of wild -type mice. The exact origin of the osteoclasts could not be ascertained . On the other hand, the increased susceptibility for CIA in TRAF6MC-KO mice could be explained by the decreased suppressive capacity of TRAF6MC -KO-derived Treg cells. Thus, TRAF6, although being an important signali ng molecule in RANKL-induced osteoclastogenesis, can also counterregulat e CIA by inducing Treg cell activity. All together, the findings described in this thesis fit in the field of osteoimmunology, i.e. the interaction between the immune and skeletal sy stem. On the one hand we demonstrated that adjuvant and IL-22 can drive and promote systemic osteoclastogenesis and arthritis, while Treg cells are able to counteract these processes. On the other hand we also pinpoi nted TRAF6, an important signaling molecule in osteoclastogenesis, as a necessary factor in the generation of fully active Treg cellsstatus: Publishe
Immunoregulatorische aspecten van interferon-γ in collageen-geïnduceerdeartritis : effecten op de activiteit van CD4+ CD25+ regulatorische T cellen en de infiltratie van neutrofiele granulocyten
No full textOver a period of several years, work in our laboratory has addressed the role of interferon-g (IFN-g) in collagen-induced arthritis (CIA), a well-characterized experimental model for rheumatoid arthritis (RA) in humans. Mice lacking a functional IFN-g receptor (IFN-gR KO) were found to be more susceptible to CIA than wild-type mice: disease onset is accelerated and arthritic symptoms are more severe. CD4+CD25+ regulatory T (Treg) cells have proven to be important in the control of various autoimmune diseases. In addition, aggrevated disease in IFN-gR KO mice is associated with a high proportion of neutrophils in the joints. In this thesis we therefore investigated the possibilities that IFN-g exerts its protective effect in CIA through stimulation of Treg cells or through inhibition of neutrophil-specific chemokines.
By rendering wild-type mice deficient in Treg cells and by a single transfer of Treg cells in wild-type mice, we demonstrated the importance of Treg cells in the pathogenesis of CIA. Wild-type mice treated with depleting anti-CD25 antibodies developed a significantly more severe arthritis, comparable to the disease course in IFN-gR KO mice. Thus, we proposed that the higher susceptibility of IFN-gR KO mice to CIA might be ascribed to defects in the production or function of these Treg cells. Having demonstrated that IFN-g receptor deficiency did not affect the number of CD4+CD25+ cells in the central and peripheral lymphoid tissues, nor their potential to suppress effector T (Teff) cell proliferation in vitro, we examined the effect of immunization on Treg cell numbers and function. After immunization with collagen type II (CII) in complete Freund’s adjuvant (CFA), the capacity of Treg cells to suppress TCR-triggered proliferation of Teff cells was significantly lower as compared to that of naive Treg cells. In addition, suppressive activity of Treg cells became significantly more impaired in the absence of IFN-g signaling. Accordingly, expression of Foxp3, a highly specific marker for Treg cells, was lower in Treg cells obtained from immunized IFN-gR KO mice. We completed this part of the study by showing that the effect of endogenous IFN-g, which accounts for the more suppressive activity in immunized wild-type as compared to IFN-gR KO mice, concerns both Treg cells and accessory cells. Together, these data demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-g.
Since a single transfer of Treg cells significantly improved clinical symptoms of arthritis without affecting humoral responses, we investigated whether the effects of Treg cells in CIA may rely on the inhibition of osteoclastogenesis, a major pathogenic process in CIA. Osteoclast differentiation was found to be significantly decreased in the presence of Treg cells. Inhibition of osteoclastogenesis was accompanied by increased expression levels of cytokines inhibiting osteoclastogenesis, including granulocyte macrophage colony-stimulating factor (GM-CSF), IL-5 and IL-10. These data provide an explanation for the beneficial effect of Treg cells in CIA and suggest that Treg cells may be used for the treatment of RA.
In a subsequent part of our work we investigated the mechanism underlying the excessive proportion of neutrophils in the inflammatory lesions of IFN-gR KO mice. Neutrophils are considered important in the pathogenesis of CIA, for example by their ability to destroy cartilage. We documented significantly increased levels of myeloperoxidase and matrix metalloproteinase-9 in synovia of arthritic IFN-gR KO mice as compared to wild-type counterparts, thereby quantificating the higher infiltration of neutrophils in the joints of IFN-gR KO mice. The excessive proportion of neutrophils in synovia of arthritic IFN-gR KO mice could be explained by significantly increased levels of the CXC chemokine granulocyte chemotactic protein-2 (GCP-2), a major neutrophil-attracting chemokine in mice that is considered to be the functional equivalent of IL-8 in humans. We further demonstrated that heat-killed mycobacteria present in CFA elicit production of GCP-2 in mouse embryo fibroblast (MEF) cultures, and that this production is inhibited by IFN-g. Inhibition of GCP-2 production by IFN-g was found to be signal transducer and activator of transcription-1 (STAT-1) dependent. In addition we found that IL-17, known to be important in the pathogenesis of arthritis, synergizes with mycobacteria for the production of GCP-2. Again, IFN-g was found to inhibit this production of GCP-2. IFN-gR KO mice treated with neutralizing anti-GCP-2 antibodies were completely protected from CIA, indicating the in vivo importance of GCP-2 in the pathogenesis of CIA. These data support the notion that one of the mechanisms whereby endogenous IFN-g mitigates the manifestations of CIA consists in inhibiting production of GCP-2, thereby limiting mobilisation and infiltration of neutrophils, which are important actors in joint inflammation.
To summarize our investigations, we can state that IFN-g exerts its protective effect in CIA in part by inhibition of the decrease in Treg cell activity elicited by immunization with CII in CFA. The protective effect of Treg cells in CIA could be explained by inhibition of osteoclastogenesis. In addition, IFN-g was found to limit the infiltration of neutrophils at the site of inflammation through downregulation of the production of GCP-2. Our data may provide an explanation for the protective effect of IFN-g in other autoimmune models that rely on the use of CFA.status: Publishe
Genetic and cellular characterisation of Foxp3+ regulatory T cells during health and disease
No full textRegulatory T cells (Treg) are indispensible for the prevention of devastating immune dysregulation. The work described in this thesis provides a unique new insight into regulatory T cell biology demonstrating that after partial Treg depletion, levels of IL-2 rise significantly, allowing the unaffected Treg not only to survive but also to rapidly repopulate the niche in a co-stimulation dependent manner, with a temporary overshoot in numbers. From the detailed study of the Bcl-2 family of apoptosis/survival regulators we found that Mcl-1 and Bim are essential for regulating Treg survival and apoptosis, respectively, while Bcl-XL and Bcl-2 are not. From the finding that Mcl-1 expression is influenced by IL-2 availability, we have uncovered a potential mechanism by which IL-2 is capable of regulating apoptosis levels during perturbations in the size of the Treg niche. In addition, we found that thymus-derived Treg are able to participate in a germinal centre (GC) response by adopting a phenotype reminiscent of the cells they were found to regulate: the follicular T helper subset (Tfh). We show that follicular Treg (Tfr) limit the size of the Tfh pool, thereby limiting the help to GC B cells and ensuring the generation of high affinity antibodies and protective B cell memory.status: Publishe
Natural killer cellen in systemische juveniele idiopathische artritis en macrofaag activatie syndroom
No full textSecundary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) is a life-threatening complication of several diseases, including systemic juvenile idiopathic arthritis (sJIA), characterized by systemic inflammation with cytokine storm, overactivation of immune cells and organ failure. A defect cytotoxic function of natural killer (NK) cells is a central component of the pathogenesis of HLH. These cells of the innate immune system perform cytotoxic killing of target cells and are important cytokine producers. Lower numbers and/or defective function of NK cells have been described in different autoimmune and autoinflammatory diseases as well as infections associated with HLH. These defects could explain the development of HLH as a complication. Nevertheless, it remains unclear what underlies these NK cell defects in the different pathologies. The changing inflammatory environment is one of the possible explanations for the development of a defective NK cell function, leading to uncontrolled immune activation and resulting in a higher chance of developing HLH in the underlying diseases. However, the effect of long-term stimulation with cytokines and other immune mediators on the activation of NK cells remains unclear. This project aims to clarify the role of NK cells in relation to NK-stimulating cytokines in inflammatory diseases associated with HLH.status: Publishe
Interferon-gamma and natural killer cells in systemic juvenile idiopathic arthritis and macrophage activation syndrome
No full textSystemic juvenile idiopathic arthritis (sJIA) is a severe childhood immune-inflammatory disorder characterized by arthritis, fever, rash and lymphadenopathy. About 10% of sJIA patients develop a life-threatening complication called macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis (HLH). Both disorders are characterized by a cytokine storm, with an important role for interleukin (IL)-1β, IL-6 and IL-18. The role of interferon-gamma (IFN-γ), a cytokine with both pro- and anti-inflammatory features, is not clear. Furthermore, the significance of natural killer (NK) cells, an important source of IFN‑γ, in the pathogenesis of sJIA has not been determined. To unravel the role of IFN-γ and NK cells in sJIA and MAS, we investigated IFN-γ and associated proteins in sJIA and HLH/MAS patients ex vivo and in vitro, we identified the role of indoleamine 2,3-dioxygenase (IDO) in inflammatory mouse models and we thoroughly analyzed NK cells in sJIA patients and in a mouse model of sJIA.
In Chapter 1 it was demonstrated that patients with active sJIA and HLH/MAS show distinct cytokine profiles with equally elevated plasma levels of IL-6 and IL-18 but with highly increased levels of IFN-g and IFN-g-induced proteins (IP‑10/CXCL-10, IL-18BP and IDO) typically found in HLH/MAS and increased free IL-18 in sJIA. In addition to peripheral blood mononuclear cells, which showed an in vitro hyporesponsiveness to IFN-γ, histiocytes, endothelial cells and fibroblasts may contribute to an IFN‑γ profile in HLH/MAS patients.
Levels of IDO, an immune-modulatory enzyme, clearly differed between sJIA and HLH/MAS patients, suggesting a possible role in disease. However, as described in Chapter 2, eliciting sJIA, MAS or virus-associated HLH in IDO1-deficient mice, did not affect disease as compared to their wild-type counterparts. In addition, in a mouse model of T cell-triggered cytokine release syndrome, no differences were observed regarding numbers of regulatory T cells, apoptosis or proliferation between IDO1-deficient and wild-type mice. We therefore hypothesize other redundant enzymes might compensate for the absence of IDO1 in these models.
Finally, in chapter 3, we observed increased IL-15 and confirmed an increased IL‑18/IFN-γ ratio in plasma of sJIA patients, while levels of NK-stimulating IL-2 and IL-12 remained unchanged. The inflammatory cytokine environment in sJIA patients affected their NK cells, causing a characteristically altered gene expression pattern. Although sJIA NK cells exhibited intact cytotoxicity and normal receptor expression, the production of IFN‑g in response to IL-18±IL-12 was defective as compared to healthy controls. In complete Freund’s adjuvant-injected wild-type mice, NK cells were an important source of IFN-γ and depletion hereof resulted in sJIA-like symptoms in a subgroup of mice, indicating a protective role of NK cells in sJIA.
In conclusion, we demonstrated that the cytokine balance shifts from an IL-18-dominant environment in sJIA patients towards a clear-cut IFN-γ profile in HLH/MAS. Increasing levels of IFN-γ compared to IL-18 may raise suspicion for development of MAS in sJIA. The inflammatory environment in sJIA affects their NK cells, causing an inflammatory transcriptional profile in these cells. In contrast to the highly elevated IL-18 plasma levels, sJIA NK cells fail to respond to IL-18, resulting in a decreased IFN-γ production. Based on the defective IL-18-induced IFN-γ production by sJIA NK cells, the accordingly low levels of IFN‑γ in sJIA patients and the protective role of IFN-γ and NK cells in an associated mouse model, we conclude that NK cells and IFN-γ need to be recognized as an important disease-limiting circuit in the pathogenesis of sJIA. In HLH/MAS on the other hand, the clear IFN-γ profile together with its pathogenic role in several HLH/MAS mouse models led to the initiation of clinical trials with anti-IFN-γ antibodies. However, given IFN-γ’s anti-inflammatory properties, its presumably protective role in sJIA and two case reports in which HLH developed in IFN-γ receptor deficient patients, we suggest these treatment strategies should be monitored with caution and other possible targets for treatment should still be further investigated. In addition, we propose that further research should focus on the potential regulatory role of NK cells in auto-inflammatory disorders.status: Publishe
PENTA: A Paediatric Network Around Trauma. Registry andevaluation of circumstances and modalities of trauma andtrauma care of children and youngsters in Flanders.
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