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1.
Rheumatology (Oxford) ; 58(10): 1812-1817, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31070229

RESUMO

OBJECTIVES: To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness. METHODS: Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed. RESULTS: Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75-56), the JADAS-71 (24.5-11.0) and the cJADAS10 (18.0-10.6). CONCLUSION: MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the 'failing' biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features. TRIAL REGISTRATION: Trial register.nl, http://https://www.trialregister.nl, NTR4146.

2.
Ann Rheum Dis ; 78(8): 1107-1113, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31005900

RESUMO

OBJECTIVES: The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases. METHODS: Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst ) or polyarticular disease (SJIA poly ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst , n=45; SJIA poly , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays. RESULTS: Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly ) and 77% (SJIA syst vs infection) of all cases. CONCLUSIONS: Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.

3.
Arthritis Rheumatol ; 71(7): 1163-1173, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30848528

RESUMO

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage. METHODS: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped. RESULTS: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL-1Ra was equally effective in systemic JIA patients without arthritis at disease onset. CONCLUSION: Treatment to target, starting with first-line, short-course monotherapy with rIL-1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage in systemic JIA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Substituição de Medicamentos , Etanercepte/uso terapêutico , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Contagem de Leucócitos , Masculino , Metotrexato/uso terapêutico , Neutrófilos , Prednisolona/uso terapêutico , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
4.
Pharmaceuticals (Basel) ; 12(1)2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625990

RESUMO

Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate⁻cyclohydrolase-1 (GTP⁻CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation.

5.
Arthritis Rheumatol ; 70(6): 943-956, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29426067

RESUMO

OBJECTIVE: Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation. METHODS: Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls. RESULTS: Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1ß on neutrophils from healthy subjects. CONCLUSION: These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Neutrófilos/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Artrite Juvenil/imunologia , Criança , Feminino , Humanos , Masculino , Países Baixos , Estudos Prospectivos , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Resultado do Tratamento
6.
Ann Rheum Dis ; 77(3): 336-342, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29138257

RESUMO

OBJECTIVES: To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX). METHODS: Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated. RESULTS: Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%-75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate. CONCLUSIONS: The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/diagnóstico , Metotrexato/uso terapêutico , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Artrite Juvenil/tratamento farmacológico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento , Escala Visual Analógica
7.
Rheumatology (Oxford) ; 56(10): 1694-1699, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28957547

RESUMO

Objectives: JIA is an autoimmune disease involving disturbed T-cell homeostasis, marked by highly activated effector T cells. Autophagy, a lysosomal degradation pathway, is crucial for maintaining cellular homeostasis by regulating the survival, differentiation and function of a large variety of cells, including T cells. The aim of this study was to examine the rate of autophagy in JIA T cells and to investigate the effect of inhibition of autophagy on the inflammatory phenotype of JIA T cells. Methods: Autophagy-related gene expression was analysed in CD4+ T cells from the SF of JIA patients and healthy controls using RNA sequencing. Autophagy was measured by flow cytometry and western blot. The effect of inhibition of autophagy, using HCQ, on the cellular activation status was analysed using flow cytometry and multiplex immunoassay. Results: Autophagy was increased in T cells derived from the site of inflammation compared with cells from the peripheral blood of patients and healthy controls. This increase in autophagy was not induced by JIA SF, but is more likely to be the result of increased cellular activation. Inhibition of autophagy reduced proliferation, cytokine production and activation marker expression of JIA SF-derived CD4+ T cells. Conclusion: These data indicate that autophagy is increased in JIA SF-derived T cells and that targeting autophagy could be a promising therapeutic strategy to restore the disrupted T-cell homeostasis in JIA.


Assuntos
Artrite Juvenil/imunologia , Autofagia/imunologia , Linfócitos T CD4-Positivos/fisiologia , Líquido Sinovial/citologia , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
8.
Vaccine ; 35(21): 2818-2822, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28412076

RESUMO

OBJECTIVE: To assess humoral and cellular responses to live-attenuated varicella zoster virus (VZV) vaccination of patients with juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) or juvenile scleroderma (JScle) compared to those of healthy controls (HC). METHODS: Before, 4-6weeks and one year after VZV vaccination, blood samples of patients and HC were collected. VZV-specific antibody concentrations were measured by ELISA and multiplex immune-assay. IFN-γ ELISpot assays were performed to assess VZV-specific T-cell responses. Cytokine production upon VZV stimulation were measured with a Luminex-assay. RESULTS: 49 patients (39 JIA, 5 JDM, 5 JScle) and 18 HC were included. All patients used methotrexate (MTX), 16 also used corticosteroids, 3 patients used biologics. No disease flares were reported after vaccination. Antibody response to the vaccine was similar in patients and controls (p=0.139). Use of immunosuppressive drugs did not affect the response (p=0.203). A second vaccination (n=21) increased VZV-specific antibody concentrations (p=0.02). VZV-specific T-cells increased after vaccination (p=0.043), with a cytokine profile suggesting a VZV-specific Th1 and cytotoxic T-cell response. CONCLUSION: The humoral response to VZV vaccination in patients with pediatric rheumatic diseases (PRD) is similar to that of HC. Generally, patients are able to mount a VZV-specific cellular response. This study has been registered in the Brazilian Clinical Trials Registry under number U1111-1189-9837.


Assuntos
Vacina contra Varicela/imunologia , Varicela/prevenção & controle , Imunidade Celular , Imunossupressores/uso terapêutico , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Adolescente , Anticorpos Antivirais/sangue , Vacina contra Varicela/administração & dosagem , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral , Imunoensaio , Masculino , Linfócitos T/imunologia , Resultado do Tratamento
9.
Pediatr Rheumatol Online J ; 14(1): 55, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27650128

RESUMO

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The pathogenesis of JIA is thought to be the result of a combination of host genetic and environmental triggers. However, the precise factors that determine one's susceptibility to JIA remain to be unravelled. The microbiome has received increasing attention as a potential contributing factor to the development of a wide array of immune-mediated diseases, including inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis. Also in JIA, there is accumulating evidence that the composition of the microbiome is different from healthy individuals. A growing body of evidence indeed suggests that, among others, the microbiome may influence the development of the immune system, the integrity of the intestinal mucosal barrier, and the differentiation of T cell subsets. In turn, this might lead to dysregulation of the immune system, thereby possibly playing a role in the development of JIA. The potential to manipulate the microbiome, for example by faecal microbial transplantation, might then offer perspectives for future therapeutic interventions. Before we can think of such interventions, we need to first obtain a deeper understanding of the cause and effect relationship between JIA and the microbiome. In this review, we discuss the existing evidence for the involvement of the microbiome in JIA pathogenesis and explore the potential mechanisms through which the microbiome may influence the development of autoimmunity in general and JIA specifically.


Assuntos
Artrite Juvenil , Autoimunidade , Microbiota/imunologia , Artrite Juvenil/imunologia , Artrite Juvenil/microbiologia , Humanos
10.
Eur J Immunol ; 46(9): 2068-77, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27461267

RESUMO

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA.


Assuntos
Artrite Juvenil/etiologia , Artrite Juvenil/metabolismo , Biomarcadores , Animais , Artrite Juvenil/diagnóstico , Artrite Juvenil/terapia , Gerenciamento Clínico , Humanos , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento
11.
Genom Data ; 7: 14-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26981351

RESUMO

For many autoimmune diseases, the underlying mechanism is still unknown. In order to get more insight into the etiology of autoimmune diseases, we recently published a study were we performed epigenetic profiling and RNA sequencing on CD4(+)CD45RO(+) T cells derived from the site of inflammation of Juvenile Idiopathic Arthritis (JIA) patients and compared this with healthy controls [1]. In this "Data in Brief", we focus on the analysis of our RNA sequencing data reported in this study, of which the raw and processed files can be found in GEO under GSE71595. We provide a detailed description of the downstream analysis, quality controls, and different analysis methods or techniques that validate the results obtained with RNA-sequencing.

12.
Proteomics Clin Appl ; 10(6): 691-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26332844

RESUMO

PURPOSE: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel. EXPERIMENTAL DESIGN: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naïve were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan). RESULTS: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of 1129 proteins. The combined data from these techniques gave reproducible quantification of 1501 proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility.


Assuntos
Artrite Psoriásica/diagnóstico , Artrite Reumatoide/diagnóstico , Proteínas Sanguíneas/metabolismo , Adulto , Artrite Psoriásica/sangue , Artrite Psoriásica/patologia , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Biomarcadores/metabolismo , Cromatografia Líquida , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
13.
Cell Rep ; 12(12): 1986-96, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26387944

RESUMO

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Juvenil/tratamento farmacológico , Azepinas/farmacologia , Proteínas Proto-Oncogênicas/genética , Linfócitos T/efeitos dos fármacos , Triazóis/farmacologia , Artrite Juvenil/genética , Artrite Juvenil/metabolismo , Artrite Juvenil/patologia , Autoimunidade , Sequência de Bases , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Citocinas/genética , Citocinas/metabolismo , Elementos Facilitadores Genéticos/efeitos dos fármacos , Epigênese Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Memória Imunológica , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Dados de Sequência Molecular , Cultura Primária de Células , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Transdução de Sinais , Líquido Sinovial/citologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia
14.
Oncotarget ; 6(24): 20037-42, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26343524

RESUMO

Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.


Assuntos
Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Células Th17/imunologia , Adolescente , Autoimunidade/imunologia , Feminino , Humanos , Mutação , Transdução de Sinais
15.
Am J Pathol ; 184(5): 1274-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24650560

RESUMO

IL-17 and T-helper (Th)17 cells contribute to viral airway pathology in human newborns. Because umbilical cord blood T cells fail to differentiate toward the Th17 lineage in the presence of autologous antigen-presenting cells, we asked whether Th17 cells are present in young infants that experience respiratory viral infection. To this end, we analyzed tracheal aspirate samples from infant patients suffering from acute respiratory syncytial virus (RSV) infection and healthy infant controls. Acute RSV infection associates with elevated IL-17 and accumulation of CD161(+) T cells in acute RSV infected lungs. Correspondingly, local Th17 polarizing cytokines were increased. In peripheral blood, we show that Th17 cells are absent in healthy 1-month-old infants, but are present in acute RSV patients. The triggering of pathogen-associated pattern receptors TLR4 and TLR7 promotes the generation of a Th17-polarizing cytokine environment by 1-month-old infant dendritic cell (DC). We thus conclude that although Th17 cells are absent in healthy newborns, Th17 cells are present in peripheral blood and the airways of infants that experience viral infection, thereby contributing to airway immunopathology.


Assuntos
Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/imunologia , Células Th17/imunologia , Adulto , Polaridade Celular , Citocinas/biossíntese , Células Dendríticas/imunologia , Humanos , Lactente , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Infecções por Vírus Respiratório Sincicial/patologia , Receptores Toll-Like/metabolismo
17.
Arthritis Res Ther ; 15(3): 213, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23731900

RESUMO

This review summarizes the immunological consequences of biological therapies used in juvenile idiopathic arthritis (JIA). For every frequently used biological agent the characteristics are clearly specified (molecular target, isotype, registered indication for JIA, route of administration, half-life, contraindication, very common side effects, expected time of response and average cost in the first year). The emphasis of this review is on the immunological side effects that have been encountered for every separate agent in JIA populations. For each agent these adverse events have been calculated as incidence per 100 patient-years for the following categories: serious infections, tuberculosis, malignancies, response to vaccination, new-onset autoimmune diseases and development of anti-drug antibodies. There are large differences in side effects between various agents and there is a clear need for an international and standardized collection of post-marketing surveillance data of biologicals in the vulnerable group of JIA patients. Such an international pharmacovigilance database, called Pharmachild, has now been started.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Terapia Biológica/efeitos adversos , Criança , Humanos
19.
PLoS One ; 6(9): e24119, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21931651

RESUMO

BACKGROUND: To prevent harmful autoimmunity most immune responses to self proteins are controlled by central and peripheral tolerance. T cells specific for a limited set of self-proteins such as human heat shock protein 60 (HSP60) may contribute to peripheral tolerance. It is not known whether HSP60-specific T cells are present at birth and thus may play a role in neonatal tolerance. We studied whether self-HSP60 reactive T cells are present in cord blood, and if so, what phenotype these cells have. METHODOLOGY/PRINCIPAL FINDINGS: Cord blood mononuclear cells (CBMC) of healthy, full term neonates (n = 21), were cultured with HSP60 and Tetanus Toxoid (TT) to study antigen specific proliferation, cytokine secretion and up-regulation of surface markers. The functional capacity of HSP60-induced T cells was determined with in vitro suppression assays. Stimulation of CBMC with HSP60 led to CD4(+) T cell proliferation and the production of various cytokines, most notably IL-10, Interferon-gamma, and IL-6. HSP60-induced T cells expressed FOXP3 and suppressed effector T cell responses in vitro. CONCLUSION: Self-reactive HSP60 specific T cells are already present at birth. Upon stimulation with self-HSP60 these cells proliferate, produce cytokines and express FOXP3. These cells function as suppressor cells in vitro and thus they may be involved in the regulation of neonatal immune responses.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Chaperonina 60/imunologia , Sangue Fetal/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoensaio/métodos , Recém-Nascido , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Tolerância a Antígenos Próprios/imunologia
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