BACKGROUND AND AIMS: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA]. METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab. RESULTS: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test. CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.
- MeSH
- Bacteria MeSH
- Crohnova nemoc * patologie MeSH
- dítě MeSH
- infliximab farmakologie terapeutické užití MeSH
- inhibitory TNF farmakologie terapeutické užití MeSH
- lidé MeSH
- metabolom MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Juvenile idiopathic arthritis (JIA), a clinically variable disease characterized by autoimmune arthritis, affects children, and its immunopathology remains elusive. Alterations in neutrophil biology play an important role in this disease. In the present study, we aimed to explore the features of low-density neutrophils (LDNs) in patients with JIA. METHODS: Gene expression of peripheral blood mononuclear cells (PBMCs) from children with distinct subtypes of JIA was analyzed by NanoString Immunology panel. Presence of LDNs was ascertained by flow cytometry and the release of neutrophil-associated products were analyzed by LUMINEX. RESULTS: LDNs were detected in patients' peripheral blood mononuclear cells (PBMCs) after density gradient centrifugation. Transcriptomic analysis of JIA PBMCs revealed that genes related to neutrophil degranulation were markedly upregulated. The number of LDNs and level of their degranulation products increased in patients' PBMCs and correlated with serum calprotectin, but not with disease activity, sedimentation rate and C-reactive protein (CRP) levels. The phenotypes of LDNs varied from those of normal-density neutrophils and healthy donor LDNs. Phenotypical analysis revealed LDNs are immature and primed population with decreased suppressive capacity. A negative correlation between surface proteins CD62L, CD66b, and CD11b and the number of inflamed joints/JADAS was established. CONCLUSION: Our results describe LDNs as primed, degranulated, immature cells with impaired suppressive activities. This work thus contributes to the increasing body of evidence that LDNs in JIA are altered and their role in the disease immunopathogenesis and possible clinical associations should be investigated further.
- MeSH
- aktivace neutrofilů MeSH
- dítě MeSH
- juvenilní artritida * MeSH
- leukocyty mononukleární MeSH
- lidé MeSH
- neutrofily * MeSH
- průtoková cytometrie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
Myokarditida u dětí je poměrně vzácné a zároveň potenciálně závažné onemocnění. Často představuje diagnostické a terapeutické dilema, stejně tak volba diagnostických metod a jejich interpretace nemusí být vždy jednoznačná. V posledních letech stoupá význam magnetické rezonance, u které může být limitací její dostupnost. Variabilní přístup k dětem s myokarditidou je často patrný i v oblasti terapeutické. Významným příspěvkem je odborné stanovisko American Heart Association z roku 2021. Níže předkládaný přehledový článek představuje souhrn současných dostupných literárních dat.
Myocarditis in children is a relatively rare disease which often presents a dilemma that has to be faced not only by paediatric cardiologists but also paediatricians. The diagnosis often remains clinically suspected or probable. Only recent advancements in cardiac magnetic resonance have enabled us to confirm the diagno- sis. However, it may not be readily available. Scientific statement of the American Heart Association on paediatric myocarditis was published in 2021 and provides useful support for treatment. Hence, this article is a result of published guidelines.
- MeSH
- diagnostické techniky kardiovaskulární klasifikace MeSH
- dítě MeSH
- lidé MeSH
- myokarditida * diagnóza etiologie patofyziologie terapie MeSH
- vzácné nemoci diagnóza etiologie patofyziologie terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
INTRODUCTION: Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disorder with predominantly paediatric onset. Children present with multifocal osteolytic lesions accompanied by bone pain and soft tissue swelling. Patients often exhibit extraosseous co-morbidities such as psoriasis, inflammatory bowel disease, and arthritis. OBJECTIVES: Comparison of children with two different phenotypes of CRMO defined by presence or absence of extraosseous co-morbidities. METHODS: Children diagnosed with CRMO at the Motol University Hospital between 2010 and 2020 were retrospectively reviewed, and according to the absence or presence of extraosseous manifestations divided into two cohorts - bone limited CRMO and complex CRMO. The two groups were compared in terms of demographic data, age at disease onset, number and site of bone lesions, laboratory biomarker values, and need of escalation to a second-line therapy. RESULTS: Thirty-seven children (30 female, 7 male) with confirmed CRMO were included in the analysis. The mean age at disease onset was 10 years. All but 3 patients presented with multifocal disease. Twenty-three children (62%) had at least one extraosseous manifestation (13 sacroiliitis, 8 inflammatory bowel disease, 6 skin disease [acne, pustulosis, or psoriasis], 7 arthritis). Complex CRMO was associated with a significantly higher ESR rate (p = 0.0064) and CRP level (p = 0.018). The groups did not differ in number of foci or in age at disease onset. Bone lesion distribution differed between the two groups with significantly more frequent involvement of clavicle (p = 0.011) and pelvis (p = 0.038) in patients with complex CRMO. Children with complex CRMO more often needed escalation of therapy to DMARDs and biologic agents. CONCLUSION: Our data suggest that CRMO affecting solely the skeleton has milder course compared to complex CRMO with extraskeletal features. Further studies are needed to explore the clinical as well as the patient reported outcomes and promote individually tailored therapeutic strategies in both CRMO phenotypes.
- MeSH
- artritida * MeSH
- dítě MeSH
- fenotyp MeSH
- idiopatické střevní záněty * MeSH
- lidé MeSH
- nemoci chrupavky * MeSH
- nemoci kostí * MeSH
- psoriáza * MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Juvenile idiopathic arthritis (JIA) is a multifactorial autoimmune disease mediated by both adaptive and innate immunity. The role of neutrophils in the pathogenesis of autoimmune diseases is well-established; however, in JIA they are still markedly understudied. Here, we explored the neutrophil features and role of platelet-neutrophil aggregates in JIA patients and assessed the effect of TNF inhibitor (TNFi) therapy. We provide evidence of dysbalanced neutrophil subsets in JIA patients, with a shift towards immature and suppressive subpopulations that lack the cell-adhesion molecules. Correspondingly, patient sera contained high amounts of neutrophil- and platelet-related products. Transcriptomic analysis revealed neutrophil degranulation as the most affected process by TNFi therapy, which was mirrored by the decrease in degranulation products in the patient sera. Toll-like receptors -4, -7, and - 8 signaling pathways are particularly hyperresponsive in patients, but are strongly suppressed by TNFi. Overall, our study demonstrates augmented neutrophil and platelet responses in JIA patients.
- MeSH
- aktivace neutrofilů MeSH
- imunomodulace MeSH
- juvenilní artritida * MeSH
- lidé MeSH
- neutrofily MeSH
- trombocyty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Objective: Posttranslational modifications (PTMs) of proteins are crucial for regulating various biological processes. However, protein alteration via PTMs, and consequently, the creation of new epitopes, can induce abnormal autoimmune responses in predisposed individuals. Immunopathogenesis of several rheumatic diseases, including the most common childhood form, juvenile idiopathic arthritis (JIA), is associated with the generation of autoantibodies against such modified proteins. Dysregulated generation of neutrophil extracellular traps (NETs) can be a source of post-translationally altered proteins. Thus, we investigated the role of PTMs and the presence of NET-associated markers in JIA patients. Methods: We recruited 30 pediatric patients with JIA (20 with active disease and 10 in remission) and 30 healthy donors. The serum concentrations of citrullinated histone H3 (citH3), peptidyl arginine deiminases (PADs), and NET-related products were detected using ELISA, and the number of citH3+ neutrophils was assessed using flow cytometry. Results: The serum levels of citH3 and PADs were higher in active as well as in remission JIA patients than in healthy donors. Similarly, the number of citH3+ neutrophils was higher in the peripheral blood of patients with JIA, implying an enhanced process of NETosis. This was effectively reflected by elevated serum levels of NET-associated products, such as neutrophil elastase, LL37, and cell-free DNA-histone complexes. Additionally, 16.7% of active JIA patients were seropositive for carbamylated autoantibodies, the levels of which declined sharply after initiation of anti-TNFα therapy. Conclusion: Collectively, our data suggest that the accelerated process of NETosis and PTMs in JIA may result in the generation of anti-citrullinated/carbamylated autoantibodies against various epitopes later in life, which could be prevented by effectively regulating inflammation using immune therapy.
- Publikační typ
- časopisecké články MeSH
Monogenní syndromy periodických horeček představují heterogenní skupinu autoinflamatorních onemocnění zahrnující syndromy, jako jsou periodické horečky asociované s kryopyrinem (CAPS), receptorem pro tumor nekrotizující faktor (TRAPS), deficitem mevalonátkinázy (MKD/HIDS) a familiární středomořská horečka (FMF). Navzájem se odlišují patogenezí, klinickými projevy a závažností. Klíčovou roli u všech těchto syndromů ovšem hrají cytokiny z rodiny interleukinu 1 (IL-1). Inhibice zmíněných cytokinů, především IL-1, tak hraje zásadní roli v jejich léčbě. V současnosti je k dispozici řada léčivých přípravků, které se liší strukturou, mechanismem působení, účinností a spektrem nežádoucích účinků. Mezi nejdostupnější patří anakinra, kanakinumab a rilonacept. Zároveň však probíhá řada klinických hodnocení s jinými velmi nadějnými léčivy, například gevokizumabem, tadekinigem alfa či tranilastem. V následujícím přehledu přinášíme nový pohled na účinnost a bezpečnost inhibitorů IL-1, který poskytly výsledky recentních klinických studií.
Monogenic periodic fever syndromes are heterogeneous group of autoinflammatory diseases including distinct syndromes, such as cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor alpha receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). Individual diseases differ in pathogenesis, clinical manifestations, and severity. However, cytokines from the interleukin 1 (IL-1) family play a key role in all of them. Inhibition of these cytokines, especially IL-1, thus plays a crucial role in their treatment. At present, we have a wide range of drugs that differ in structure, mechanism of action, efficacy, and spectrum of side effects. The most available are anakinra, canakinumab and rilonacept. Moreover, several clinical trials are currently underway with other very promising drugs, such as gevokizumab, tadekinig alfa or tranilast. In the following review, we provide a new perspective on the efficacy and safety of IL-1 inhibitors that have provided the novel results coming from recently published clinical trials.
- Klíčová slova
- kanakinumab, Rilonacept,
- MeSH
- antagonista receptoru pro interleukin 1 * imunologie terapeutické užití MeSH
- antiflogistika terapeutické užití MeSH
- dědičné zánětlivé autoimunitní nemoci * farmakoterapie imunologie patologie MeSH
- humanizované monoklonální protilátky imunologie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- periodické syndromy asociované s kryopyrinem farmakoterapie imunologie patologie MeSH
- rekombinantní fúzní proteiny imunologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
