scholarly journals A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis

2017 ◽  
Vol 214 (11) ◽  
pp. 3449-3466 ◽  
Author(s):  
Alma-Martina Cepika ◽  
Romain Banchereau ◽  
Elodie Segura ◽  
Marina Ohouo ◽  
Brandi Cantarel ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Unknown Etiology ◽  
Integrated Analysis ◽  
Cell Phenotype ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Immune Alterations

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.

scholarly journals Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

2018 ◽  
Vol 19 (12) ◽  
pp. 3762 ◽  
Author(s):  
Anaïs Wakx ◽  
Margaux Nedder ◽  
Céline Tomkiewicz-Raulet ◽  
Jessica Dalmasso ◽  
Audrey Chissey ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Human Placenta ◽  
Target Genes ◽  
Environmental Pollutants ◽  
Cell Fractionation ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Epithelial Barriers ◽  
Expression And Activity

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands.

Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome

2020 ◽  
pp. annrheumdis-2020-217470
Author(s):  
Grant S Schulert ◽  
Alex V Pickering ◽  
Thuy Do ◽  
Sanjeev Dhakal ◽  
Ndate Fall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Rna Seq ◽  
Bone Marrow Macrophage ◽  
Ifn Γ ◽  
Activation Syndrome

ObjectivesSystemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response.MethodsBulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling.ResultsBulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness.ConclusionsMacrophages with an ‘IFN-γ response’ phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.

scholarly journals Idiopathic Pulmonary Hemosiderosis in a Child with Recurrent Macrophage Activation Syndrome Secondary to Systemic Juvenile Idiopathic Arthritis

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Kenan Barut ◽  
Sezgin Sahin ◽  
Amra Adrovic ◽  
Velat Sen ◽  
Ozgur Kasapcopur
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Inflammatory Diseases ◽  
Delayed Diagnosis ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Pulmonary Hemosiderosis ◽  
Pulmonary Manifestations ◽  
Life Threatening ◽  
Activation Syndrome

Macrophage activation syndrome, a severe complication of systemic juvenile idiopathic arthritis and other inflammatory diseases, represents one of the most important rheumatological emergencies. Delayed diagnosis could lead to life-threatening complications. Pulmonary hemosiderosis has been classically characterized by a triad of anemia, hemoptysis, and lung infiltrates on chest radiogram. Although the majority of patients of pulmonary hemosiderosis are considered idiopathic, secondary hemosiderosis associated with known diseases could be seen. In this case report, we aimed to present gradually increased pulmonary manifestations due to pulmonary hemosiderosis with recurrent macrophage activation syndrome attacks in a child with systemic juvenile idiopathic arthritis.

scholarly journals Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan

2015 ◽  
Vol 75 (9) ◽  
pp. 1654-1660 ◽  
Author(s):  
Shumpei Yokota ◽  
Yasuhiko Itoh ◽  
Tomohiro Morio ◽  
Hideki Origasa ◽  
Naokata Sumitomo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Juvenile Idiopathic Arthritis ◽  
Real World ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Clinical Settings ◽  
Real World Data ◽  
Protein Levels ◽  
Reactive Protein ◽  
Serious Infections

ObjectivesTo evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan.MethodsPaediatric patients with sJIA initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks.ResultsOf 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (<0.3 mg/dL), respectively.ConclusionsThese first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study.

scholarly journals AB0019 GENETIC POLYMORPHISM OF THE INFLAMMATORY MARKER SAA1 RS12218 (-13 T/C) IS ASSOCIATED WITH AN APTITUDE TO CLINICAL PHENOTYPES OF JUVENILE IDIOPATHIC ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1312.3-1313
Author(s):  
E. Fedorov ◽  
S. Salugina ◽  
M. Krylov ◽  
I. Guseva ◽  
E. Samarkina
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Inflammatory Diseases ◽  
Inflammatory Marker ◽  
Joint Inflammation ◽  
Unknown Etiology ◽  
Control Group ◽  
Number Of Patients ◽  
Increased Risk ◽  
Allele Specific ◽  
Diagnosis And Classification

Background:Juvenile idiopathic arthritis (JIA) is one of the most widely-spread immuno-inflammatory diseases of an unknown etiology, the leading manifestation of which is chronic joint inflammation, occuring in children under the age of 16. The disease is a complex of chronic arthropathies with various phenotypic manifestations.Objectives:To verify the hypothesis about the role of SAA1 rs12218 T / C gene polymorphism in the aptitude to various clinical JIA phenotypes.Methods:The study included 132 children, of whom 66 were diagnosed with JIA and 66 were healthy unrelated volunteers (the college students) as a control group, comparable by gender and age. The group of patients with JIA consisted of 44 girls and 22 boys, with an average age of 11.7 ± 4.2 years and an average disease duration of 4.8 ± 3.8 years. The diagnosis and classification of JIA was established according to ILAR-2004 criteria. The JIA group included 30 (45%) patients with oligoarthritis (oJIA), of which 20 patients (67%) were positive for the HLA-B27 antigen (JIA-B27 +) and 10 (33%) patients with anterior uveitis (uJIA); 20 (30%) patients were assigned to the group with the polyarticular variant (pJIA), while all of them were seronegative for the rheumatoid factor; 16 (24%) patients were diagnosed with JIA with a systemic onset (sJIA). The frequencies of the T / C polymorphism of the SAA1 gene were assessed using an allele-specific polymerase chain reaction in a real time mode (RT-PCR).Results:In the group of patients diagnosed with oJIA and (JIA-B27 +), the frequency of the C allele was significantly higher compared to the control (53.3% and 57.5% versus 37.1%, p = 0.035 and 0.022, respectively). No significant differences were detected in the frequencies of the mutant C allele between sJIA and pJIA and the control group. The logistics analysis of the frequency distribution of the alleles of the SAA1 gene demonstrated an increased risk of the C allele in formation of an aptitude to the oJIA variant (OR 1.94, 95% CI 1.00-3.76, p = 0.035). In the oJIA-B27 (+) group, the risk of an aptitude was also increased compared to the control (OR 2.29, 95% CI 1.05-5.04, p = 0.022).Conclusion:The data obtained confirm for the first time the involvement of the rs12218 polymorphism of the SAA1 gene in an aptitude to the oligoarthritis JIA clinical phenotype. The presented results require further replication researches using an enlarged number of patients from different population groups.Disclosure of Interests:None declared

scholarly journals AB1002 IS KAWASAKI DISEASE OR SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS IN CHILDREN WITH FEVER WITHOUT A SOURCE?

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1794.2-1794
Author(s):  
B. Sözeri ◽  
F. Demir ◽  
T. Merter ◽  
M. Karacan
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Kawasaki Disease ◽  
Clinical Features ◽  
Systemic Vasculitis ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Clinical Feature ◽  
Unknown Etiology ◽  
Ivig Treatment ◽  
Factors Affecting ◽  
The Mean

Background:Fever without a source (FWS) is caused by various diseases, making differential diagnosis difficult. Clinical similarities between Kawasaki disease (KD) and systemic Juvenile Idiopathic Arthritis (sJIA) are well known. Kawasaki disease (KD), a self-limiting systemic vasculitis, remains of unknown etiology and can cause irreversible coronary artery aneurysms (CAAs). SoJIA is sometimes confused with incomplete KD because both diseases have overlapping clinical features and can be accompanied with CAAs and/or SJIA with macrophage activation syndrome (MAS).Objectives:In this study, the frequency of both KD and SJIA among the patients evaluated with FWS and the clinical features of patients diagnosed with Kawasaki disease.Methods:Medical records of patients who first visited our department between January 2016 and December 2019 were reviewedResults:A total of 107 patients were enrolled in this study, including 43 patients (40.2%, 23 males) who fulfilled the criteria of Kawasaki disease and 64 patients (59.8%, 39 males) who did not fulfill them. In patients who fulfilled the criteria of classical FWS, 36(33.6%, 20 males) patients were diagnosed with systemic juvenile idiopathic arthritis. The mean age of the patients with Kawasaki disease was 30.0±20,4 months (median 25 months), the mean age of other patients was 52,6±40 months (median 39,5 months). The mean age of the patients with sJIA patients was 87,6±49,8 (median 80months). Kawasaki patients were younger than others (p=0.01). There was no difference in gender between groups.In Kawasaki patients, the most common clinical feature at diagnosis was fever (100%) followed by conjunctival congestion and mucosal changes (69%). The last two findings are more significant in kawasaki patients than others (p<0,00). Twenty-six (59%) patients had completed KD while 25% had incomplete KD. 7 (16%) patients had atypical KD. The mean fever duration was longer in sJIA patients than KD and others (median 14,8 and 7 days, p<0.00). All patients with KD received IVIG (2 g/kg, infusion in 12 h) and aspirin (60 mg/kg/day). 13.6% of the patients also received oral corticosteroids because of IVIG resistance. Thirty-one patients (72.1%) responded to IVIG treatment, whereas 12 (6 female, 6 male) were IVIG resistant. CAI was detected in echocardiography at diagnosis in 10 (22.7%) (6 female; 4 male) patients. We also detected 4 patients pericarditis with /without CIA.Conclusion:The clinical presentations of KD and sJIA are quite similar with fever, rash, hepatomegaly, and lymphadenopathy. All 2 entities may provide clues to potentially shared immunopathology.References:[1]Arslanoglu Aydin E et al. The factors affecting the disease course in Kawasaki disease. Rheumatol Int. 2019 Aug;39(8):1343-1349[2]Dong S et al. Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease. J Pediatr. 2015 May;166(5):1283-8.Disclosure of Interests:None declared

scholarly journals Kawasaki Disease and Systemic Juvenile Idiopathic Arthritis – Two Ends of the Same Spectrum

2021 ◽  
Vol 9 ◽  
Author(s):  
Ellen Go ◽  
Mira van Veenendaal ◽  
Cedric Manlhiot ◽  
Rayfel Schneider ◽  
Brian W. McCrindle ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Coronary Artery ◽  
Kawasaki Disease ◽  
Macrophage Activation ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Treatment Regimens ◽  
Coronary Artery Dilatation ◽  
High Prevalence ◽  
Disease Entities

Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (sJIA) are two distinct systemic inflammatory diseases of childhood. Each diagnosis is based on criteria, but numerous clinical features are overlapping. As no specific diagnostic tests are available, differentiation between both disease entities can be challenging. Here, we describe the disease course of patients with co-diagnosis of both KD and sJIA (KD/sJIA). All our KD (n = 1765) and sJIA (n = 112) cases were critically reviewed for co-diagnosis of KD/sJIA. Eight KD/sJIA cases were identified and their clinical presentation, treatment regimens, coronary artery outcome and complications are herein described. Each KD/sJIA patient fulfilled diagnostic criteria for KD and for sJIA. Ongoing fever, rash and arthritis were present in each patient. The KD/sJIA patients had recalcitrant KD requiring multiple doses of intravenous immunoglobulin and steroids. Five patients had coronary artery dilatation at KD diagnosis, which resolved in all by 6 weeks. Pericardial effusion was present in 5 patients. One KD/sJIA patient developed macrophage activation syndrome. In conclusion, a small proportion (0.5%) of our KD patients evolved into sJIA, and 7% of our sJIA population presented initially as KD. KD/sJIA patients were characterized by a recalcitrant KD course and a high prevalence of coronary artery dilatation. Patients with co-diagnoses may provide a clue to potentially shared immunopathology in KD and sJIA, leading us to posit that both entities may be part of the same clinical spectrum.

Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation

Rheumatology ◽  
2020 ◽  
Vol 59 (10) ◽  
pp. 3099-3105 ◽  
Author(s):  
Sofie E Jørgensen ◽  
Mette Christiansen ◽  
Christian Høst ◽  
Mia Glerup ◽  
Birgitte Mahler ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Caspase 1 ◽  
Activation Syndrome

Abstract Objectives We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors. Methods Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants. Results WES revealed an extremely rare heterozygous missense variant, c.482G&gt;A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1β and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission. Conclusion For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1β and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.

scholarly journals Expression of E-cadherin and specific CXCR3 isoforms impact each other in prostate cancer

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bo Ma ◽  
Ahmad Khazali ◽  
Hanshuang Shao ◽  
Yuhan Jiang ◽  
Alan Wells
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Surface Expression ◽  
Cell Phenotype ◽  
Reciprocal Regulation ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
E Cadherin

Abstract Background Carcinoma cells shift between epithelial and mesenchymal phenotypes during cancer progression, as defined by surface presentation of the cell-cell cohesion molecule E-cadherin, affecting dissemination, progression and therapy responsiveness. Concomitant with the loss of E-cadherin during the mesenchymal transition, the predominant receptor isoform for ELR-negative CXC ligands shifts from CXCR3-B to CXCR3-A which turns this classical G-protein coupled receptor from an inhibitor to an activator of cell migration, thus promoting tumor cell invasiveness. We proposed that CXCR3 was not just a coordinately changed receptor but actually a regulator of the cell phenotype. Methods Immunoblotting, immunofluorescence, quantitative real-time PCR and flow cytometry assays investigated the expression of E-cadherin and CXCR3 isoforms. Intrasplenic inoculation of human prostate cancer (PCa) cells with spontaneous metastasis to the liver analyzed E-cadherin and CXCR3-B expression during cancer progression in vivo. Results We found reciprocal regulation of E-cadherin and CXCR3 isoforms. E-cadherin surface expression promoted CXCR3-B presentation on the cell membrane, and to a lesser extent increased its mRNA and total protein levels. In turn, forced expression of CXCR3-A reduced E-cadherin expression level, whereas CXCR3-B increased E-cadherin in PCa. Meanwhile, a positive correlation of E-cadherin and CXCR3-B expression was found both in experimental PCa liver micro-metastases and patients’ tissue. Conclusions CXCR3-B and E-cadherin positively correlated in vitro and in vivo in PCa cells and liver metastases, whereas CXCR3-A negatively regulated E-cadherin expression. These results suggest that CXCR3 isoforms may play important roles in cancer progression and dissemination via diametrically regulating tumor’s phenotype.

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