Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31710506

RESUMO

RATIONALE: Interleukin (IL) 18 is a member of the IL-1 cytokine family and elevated blood IL-18 concentrations associate with disease activity in Macrophage Activation Syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions. OBJECTIVE: While recent investigations provide mechanistic evidence for a contribution of IL-18 to (hyper)inflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression. METHODS: Samples from in vivo and in vitro endotoxin re-challenge experiments, inflammatory disease patients and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT-inhibition was analyzed in two MAS mouse models as well as a patient with recurrent MAS. MEASUREMENTS AND MAIN RESULTS: Peripheral blood as well as monocytic IL-18 expression escaped lipopolysacharide (LPS)-induced immunoparalysis. LPS-stimulated primary human monocytes revealed a specific IL-18 expression kinetics controlled by IFNα/ß-signaling. JAK/STAT-inhibition or IFNß-neutralization during LPS-stimulation blunted cytokine expression. Similarly, microtubule destabilizing drugs abrogated LPS-induced IL18 expression, which could be fully reversed by addition of IFNα/ß. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I interferon score and IL18 expression, while JAK/STAT-inhibition in two MAS mouse models as well as a patient with recurrent MAS strongly reduced IL-18 serum levels. CONCLUSION: Our data indicate that IL-18 (but not IL-1ß) production from human monocytes requires cooperate toll-like receptor and IFNα/ß-signaling. Interference with IFNα/ß-expression or signaling following JAK/STAT-inhibition may control catastrophic hyperinflammation in MAS. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

2.
Arthritis Rheumatol ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599092

RESUMO

OBJECTIVE: To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response. METHODS: Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed. RESULTS: Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years). CONCLUSION: The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment).

3.
Curr Rheumatol Rep ; 20(9): 53, 2018 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-30008153

RESUMO

PURPOSE OF REVIEW: Current technical advances enable the assessment of the complex changes in body fluid proteomes and thus allow for the discovery of biomarker signatures rather than just following differences of a single marker. In this review, we aim to summarize current approaches to discover and evaluate multi-biomarker panels for improved monitoring of chronic arthritis disease activity. RECENT FINDINGS: Mass spectrometry and affinity proteomic methodologies have been used to identify biomarker panels in synovial fluid, serum, plasma, or urine of pediatric and adult chronic arthritis patients. Notably, despite the numerous efforts to develop new and better biomarker panels, very few have undergone extensive analytical and clinical validation and been adopted into routine use for patient benefit. There remains a significant gap between discovery of chronic arthritis biomarker signatures and their validation for clinical use.


Assuntos
Artrite/diagnóstico , Biomarcadores/análise , Proteômica/métodos , Doença Crônica , Humanos , Espectrometria de Massas/métodos , Reprodutibilidade dos Testes
5.
J Clin Invest ; 128(7): 3041-3052, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29649002

RESUMO

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.


Assuntos
Azetidinas/uso terapêutico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interferons/antagonistas & inibidores , Interferons/metabolismo , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Ensaios de Uso Compassivo , Feminino , Doenças Hereditárias Autoinflamatórias/enzimologia , Humanos , Lactente , Inflamação/enzimologia , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Masculino , Estudos Prospectivos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
6.
Pediatr Rheumatol Online J ; 16(1): 7, 2018 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357887

RESUMO

BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.


Assuntos
Artrite Juvenil/diagnóstico , Padrões de Prática Médica/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Criança , Pré-Escolar , Consenso , Bases de Dados Factuais , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Sistema de Registros
7.
Rheumatology (Oxford) ; 56(9): 1597-1606, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859329

RESUMO

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future. Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA. Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease. Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.


Assuntos
Colchicina/administração & dosagem , Febre Familiar do Mediterrâneo/tratamento farmacológico , Adolescente , Fatores Etários , Antropometria/métodos , Biomarcadores/sangue , Superfície Corporal , Criança , Pré-Escolar , Colchicina/efeitos adversos , Colchicina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Humanos , Masculino , Prognóstico , Sistema de Registros , Proteínas S100/sangue , Índice de Gravidade de Doença
8.
Pediatr Rheumatol Online J ; 15(1): 19, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381287

RESUMO

BACKGROUND: Systemic autoinflammatory diseases (SAIDs) represent a growing number of monogenic, polygenic or multifactorial disorders that are often difficult to diagnose. CASE PRESENTATION: Here we report a patient who was initially erroneously diagnosed and treated for SAID. Symptoms consisted of recurrent fever, erythematous and/or blistering skin lesions, angioedema, susceptibility to bleeding, external ear infections and reversible anisocoria in the absence of laboratory evidence of systemic inflammation. After two and a half years of extensive diagnostic work-up and multiple empirical therapies, a final diagnosis of Munchausen by proxy syndrome (MBPS) was established. CONCLUSIONS: The diagnosis of SAID needs to be carefully reassessed if measurable systemic inflammation is missing, and MBPS should be included in the differential diagnosis.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Síndrome de Munchausen Causada por Terceiro/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Humanos , Masculino
9.
Arthritis Rheumatol ; 69(7): 1480-1494, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28296284

RESUMO

OBJECTIVE: Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1ß (IL-1ß) as a key cytokine and a second chronic arthritic phase that may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing γ/δ T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17-producing cells are still unclear. METHODS: Serum samples from systemic JIA patients and healthy pediatric controls were analyzed for the levels of IL-17A and related cytokines. Whole blood samples were studied for cellular expression of IL-17 and interferon-γ (IFNγ). CD4+ and γ/δ T cells isolated from the patients and controls were assayed for cytokine secretion in different culture systems. RESULTS: IL-17A was prevalent in sera from patients with active systemic JIA, while both ex vivo and in vitro experiments revealed that γ/δ T cells overexpressed this cytokine. This was not seen with CD4+ T cells, which expressed strikingly low levels of IFNγ. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Furthermore, culturing healthy donor γ/δ T cells in serum from systemic JIA patients or in medium spiked with IL-1ß, IL-18, and S100A12 induced IL-17 overexpression at levels similar to those observed in the patients' cells. CONCLUSION: A systemic JIA cytokine environment may prime γ/δ T cells in particular for IL-17A overexpression. Thus, our observations in systemic JIA patients strongly support a pathophysiologic role of these cells, as proposed by the recent murine model.


Assuntos
Artrite Juvenil/imunologia , Interleucina-17/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-18/imunologia , Interleucina-18/farmacologia , Interleucina-1beta/imunologia , Interleucina-1beta/farmacologia , Subunidade p19 da Interleucina-23/imunologia , Interleucina-6/imunologia , Masculino , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Proteína S100A12/imunologia , Proteína S100A12/farmacologia , Linfócitos T/metabolismo , Adulto Jovem
10.
Int Immunopharmacol ; 44: 216-225, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28126686

RESUMO

Glycogen storage disease type Ib (GSD-Ib) is characterized by impaired glucose homeostasis, neutropenia and neutrophil dysfunction. Mass spectrometric glycomic profiling of GSD-Ib neutrophils showed severely truncated N-glycans, lacking galactose. Experiments indicated the hypoglycosylation of the electron transporting subunit of NADPH oxidase, which is crucial for the defense against bacterial infections. In phosphoglucomutase 1 (PGM1) deficiency, an inherited disorder with an enzymatic defect just one metabolic step ahead, hypogalactosylation can be successfully treated by dietary galactose. We hypothesized the same pathomechanism in GSD-Ib and started a therapeutic trial with oral galactose and uridine. The aim was to improve neutrophil dysfunction through the correction of hypoglycosylation in neutrophils. The GSD-Ib patient was treated for 29weeks. Monitoring included glycomics analysis of the patient's neutrophils and neutrophil function tests including respiratory burst activity, phagocytosis and migration. Although no substantial restoration of neutrophil glycosylation was found, there was partial improvement of respiratory burst activity.


Assuntos
Antiporters/genética , Galactose/uso terapêutico , Glucose/metabolismo , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Proteínas de Transporte de Monossacarídeos/genética , NADPH Oxidases/metabolismo , Neutrófilos/efeitos dos fármacos , Administração Oral , Feminino , Genótipo , Doença de Depósito de Glicogênio Tipo I/genética , Glicosilação/efeitos dos fármacos , Humanos , Hipoglicemia/genética , Lactente , Neutrófilos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
11.
Joint Bone Spine ; 84(4): 401-410, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27659403

RESUMO

Alarmins are endogenous molecules with homeostatic roles that have reached the focus of research in inflammatory arthritis in the last two decades, mostly due to their ability to indicate tissue related damage after active or passive release from injured cells. From HMGB1, S100A8/A9 and S100A12 proteins, over heat-shock proteins (HSPs) and purine metabolites (e.g. uric acid, ATP) to altered matrix proteins and interleukin-33 (IL-33), a number of alarmins have been determined until now as having a role in rheumatoid arthritis, psoriatic and juvenile idiopathic arthritis, as well as spondyloarthritis and gout. Although formerly being linked to initiation and chronification of inflammatory arthritis, driving auto- and paracrine inflammatory loops, more recent research has also unraveled the alarmins' role in the crosstalk between innate and adaptive immunity and in resolution of inflammation. Providing a state-of-the-art overview of known alarmins, this review lists the known modes of action and pathologic contribution of alarmins to inflammatory arthritis, as well as biomarker potential of alarmins in the clinical setting for tracking disease severity. Based upon research on animal experimental models (CIA, AIA) and clinical trials, a look is made into potentially viable strategies for modifying alarmin secretion and their target receptor (e.g. TLR, RAGE) interaction with the purpose of attenuating arthritic disease.


Assuntos
Alarminas/fisiologia , Artrite/diagnóstico , Alarminas/sangue , Animais , Artrite/sangue , Artrite/fisiopatologia , Biomarcadores/sangue , Modelos Animais de Doenças , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/fisiopatologia
12.
Arthritis Rheumatol ; 68(12): 3010-3022, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27333294

RESUMO

OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF. METHODS: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1ß, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1ß were also analyzed in 128 clinically and genetically characterized patients with FMF. RESULTS: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease. CONCLUSION: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.


Assuntos
Caspase 1/metabolismo , Febre Familiar do Mediterrâneo/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Neutrófilos/metabolismo , Pirina/genética , Proteína S100A12/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Caspase 1/sangue , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/imunologia , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Técnicas In Vitro , Interleucina-18/sangue , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Proteína S100A12/sangue , Adulto Jovem
13.
Clin Exp Rheumatol ; 33(6 Suppl 94): S113-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26486615

RESUMO

OBJECTIVES: To assess subclinical inflammation in heterozygous carriers of Mediterranean fever (MEFV) gene mutations, analysis of classical inflammation markers and S100A12 was performed. METHODS: Exons 2, 3, and 10 of the MEFV gene, C-reactive protein (CRP), serum amyloid A protein (SAA), procalcitonin (PCT), and S100A12 concentrations, erythrocyte sedimentation rate (ESR), and differential blood count were analysed in apparently healthy parents (n=26) of homozygous children with familial Mediterranean fever (FMF). Their general health condition was assessed by a standardised questionnaire. In order to collect data on the disease course, subjects were reevaluated after 5 years by means of telephone interview and/or questionnaire. RESULTS: Twenty-two individuals with one typical mutation in the MEFV gene were included. Mean values (mean±SEM) of classical inflammation markers were within the normal range (ESR of 11.7±1.9 mm/h, SAA 4.7±0.4 mg/l, CRP 0.26±0.04 mg/dl), while PCT was non-detectable in all cases (<0.1 µg/l). Eleven subjects showed elevated S100A12 levels [>140 ng/ml] with a mean concentration of 205±43 ng/ml. Thus, the mean value of S100A12 was 1.5-fold higher than the regular cut-off. CONCLUSIONS: 50% of the heterozygous MEFV mutation carriers exhibited elevated S100A12 levels, supporting previous observations that S100 molecules are very sensitive biomarkers of subclinical inflammation. Possibly, S100A12 could be a prognostic biomarker to detect individuals at risk of FMF manifestation who might benefit from colchicine therapy.


Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/genética , Heterozigoto , Mediadores da Inflamação/sangue , Mutação , Proteína S100A12/sangue , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Sedimentação Sanguínea , Análise Mutacional de DNA , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Pirina , Inquéritos e Questionários , Fatores de Tempo , Regulação para Cima
14.
J Immunol ; 193(7): 3355-65, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25187661

RESUMO

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 development, emphasizing the role of S100 proteins in Th17-triggered inflammation. Altogether, our results indicate that induction of Th17 cells by activated monocytes and the stimulatory effects of proinflammatory S100 proteins might play a relevant role in the pathogenesis of acute GvHD. Regarding our data, S100 proteins might be novel markers for the diagnosis and follow-up of GvHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Monócitos/imunologia , Proteínas S100/imunologia , Células Th17/imunologia , Doença Aguda , Adolescente , Adulto , Biomarcadores/sangue , Células Cultivadas , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Masculino , Monócitos/metabolismo , Monócitos/patologia , Proteínas S100/sangue , Células Th17/metabolismo , Células Th17/patologia
15.
Int J Med Sci ; 11(11): 1140-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25170297

RESUMO

BACKGROUND: Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease associated with subclinical inflammation, which includes atherosclerosis arising from endothelial inflammation, which in turn increases the risk of atrial or ventricular arrhythmias. Conduction abnormalities can be detected using the electrocardiographic (ECG) indices P and QT dispersion (Pdisp and QTdisp). Currently, it is unknown whether patients with FMF are more likely to have abnormalities of these ECG indices. Moreover, existing studies were conducted in countries with higher FMF prevalence. We therefore perform the first prospective study assessing Pdisp and QTdisp in adult FMF patients in Germany, where prevalence of FMF is low. METHOD: Asymptomatic FMF patients (n=30) of Turkish ancestry living in Germany and age-matched healthy controls (n=37) were prospectively assessed using 12-lead ECG. RESULTS: Patients and controls were comparable in gender and body mass index, and patients had higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) compared to controls (ESR: 23.7±14.3 vs. 16.1±13,3 mm/1(st)h, p=0.03, CRP: 0.73±0.9 vs. 0.26±0.4 g/dl, p=0.01, SAA: 3.14±4,8 vs. 0.37±0.3 mg/dl, p<0.01). No statistically significant difference between patients and controls respectively, for Pdisp (43.7±11.9 vs. 47.1±11.2ms, p=0.23), QTdisp (65.9±12.3 vs. 67.6±12.7 ms, p=0.58) or corrected QTdisp (cQTdisp: 73.9±15.0 vs. 76.0±13.3 ms, p=0.55) was found. No correlation could be found between Pdisp or QTdisp or cQTdisp and any of the biochemical markers of inflammation. CONCLUSION: FMF patients living in Germany show a Pdisp and QTdisp comparable to healthy controls, with no increased risk of atrial or ventricular arrhythmias indicated.


Assuntos
Febre Familiar do Mediterrâneo/fisiopatologia , Adulto , Idoso , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Eletrocardiografia , Febre Familiar do Mediterrâneo/metabolismo , Febre Familiar do Mediterrâneo/patologia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/metabolismo , Migrantes
16.
J Allergy Clin Immunol ; 134(1): 155-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24767876

RESUMO

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare form of autosomal recessive combined primary immunodeficiency caused by a enzyme defect leading to the accumulation of inosine, 2'-deoxy-inosine (dIno), guanosine, and 2'-deoxy-guanosine (dGuo) in all cells, especially lymphocytes. Treatments are available and curative for PNP deficiency, but their efficacy depends on the early approach. PNP-combined immunodeficiency complies with the criteria for inclusion in a newborn screening program. OBJECTIVE: This study evaluate whether mass spectrometry can identify metabolite abnormalities in dried blood spots (DBSs) from affected patients, with the final goal of individuating the disease at birth during routine newborn screening. METHODS: DBS samples from 9 patients with genetically confirmed PNP-combined immunodeficiency, 10,000 DBS samples from healthy newborns, and 240 DBSs from healthy donors of different age ranges were examined. Inosine, dIno, guanosine, and dGuo were tested by using tandem mass spectrometry (TMS). T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels were evaluated by using quantitative RT-PCR only for the 2 patients (patients 8 and 9) whose neonatal DBSs were available. RESULTS: Mean levels of guanosine, inosine, dGuo, and dIno were 4.4, 133.3, 3.6, and 3.8 µmol/L, respectively, in affected patients. No indeterminate or false-positive results were found. In patient 8 TREC levels were borderline and KREC levels were abnormal; in patient 9 TRECs were undetectable, whereas KREC levels were normal. CONCLUSION: TMS is a valid method for diagnosis of PNP deficiency on DBSs of affected patients at a negligible cost. TMS identifies newborns with PNP deficiency, whereas TREC or KREC measurement alone can fail.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Mutação , Purina-Núcleosídeo Fosforilase/deficiência , Purina-Núcleosídeo Fosforilase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Adolescente , Pré-Escolar , Reparo do DNA , Desoxiguanosina/análise , Desoxiguanosina/metabolismo , Teste em Amostras de Sangue Seco , Feminino , Guanosina/análise , Guanosina/metabolismo , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Inosina/análogos & derivados , Inosina/análise , Inosina/metabolismo , Linfócitos/patologia , Masculino , Triagem Neonatal , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/patologia , Espectrometria de Massas em Tandem
17.
Arthritis Care Res (Hoboken) ; 66(6): 949-55, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24339418

RESUMO

OBJECTIVE: The myeloid-related proteins 8 and 14 (MRP-8/MRP-14) and neutrophil-derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme-linked immunosorbent assays (ELISAs) in order to validate systems available for routine use. METHODS: MRP-8/MRP-14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed. RESULTS: For MRP-8/MRP-14, the PhiCal Calprotectin and Buhlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN-RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs. CONCLUSION: For the prediction of JIA relapse after stopping medication, the biomarkers MRP-8/MRP-14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP-8/MRP-14 and S100A12 ELISAs showed a performance comparable to well-established experimental ELISA protocols when assay-specific cutoffs for the indication of relapse prediction are thoroughly applied.


Assuntos
Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Calgranulina A/sangue , Calgranulina B/sangue , Proteínas S100/sangue , Adulto , Antirreumáticos/uso terapêutico , Artrite Juvenil/diagnóstico , Biomarcadores/sangue , Criança , Ensaio de Imunoadsorção Enzimática/normas , Feminino , Humanos , Masculino , Fatores de Risco , Proteína S100A12 , Prevenção Secundária
18.
Arthritis Res Ther ; 15(5): R131, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24286299

RESUMO

INTRODUCTION: The aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood. In particular the contribution of monocytes or macrophages, which are frequently observed to be an infiltrate within muscle tissue very early in the disease process, is unknown. We hypothesised that these cells secrete the pro-inflammatory myeloid related protein (MRP) 8/14 which may then contribute to muscle pathology in JDM. METHODS: In this study of 56 JDM patients, serum MRP8/14 levels were compared with clinical measures of disease activity. Muscle biopsies taken early in disease were assessed by immunohistochemistry to determine the frequency and identity of MRP-expressing cells. The effects of MRP stimulation and endoplasmic reticulum (ER) stress on muscle were tested in vitro. Serum or supernatant levels of cytokines were analyzed by multiplex immunoassay. RESULTS: Serum MRP8/14 correlated with physician's global assessment of disease activity in JDM (R = 0.65, p = 0.0003) and muscle strength/endurance, childhood myositis assessment score (CMAS, R = -0.55, p = 0.004). MRP8/14 was widely expressed by CD68+ macrophages in JDM muscle tissue. When cultured with human myoblasts, MRP8 led to the secretion of MCP-1 and IL-6, which was enhanced by ER stress. Both inflammatory mediators were detected in significantly higher levels in the serum of JDM patients compared to healthy controls. CONCLUSIONS: This study is the first to identify serum MRP8/14 as a potential biomarker for disease activity in JDM. We propose that tissue infiltrating macrophages secreting MRP8/14 may contribute to myositis, by driving the local production of cytokines directly from muscle.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Dermatomiosite/metabolismo , Mediadores da Inflamação/metabolismo , Músculos/metabolismo , Adolescente , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biópsia , Calgranulina A/sangue , Calgranulina B/sangue , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Citocinas/metabolismo , Dermatomiosite/sangue , Dermatomiosite/patologia , Estresse do Retículo Endoplasmático , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Microscopia de Fluorescência , Força Muscular , Músculos/patologia , Músculos/fisiopatologia , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Arthritis Res Ther ; 15(3): R64, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23718630

RESUMO

OBJECTIVES: Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1ß monoclonal antibody, can abolish excess IL-1ß. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. METHODS: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. RESULTS: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. CONCLUSIONS: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
20.
Am J Respir Crit Care Med ; 187(12): 1324-34, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23611140

RESUMO

RATIONALE: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. OBJECTIVES: We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. METHODS: Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. MEASUREMENTS AND MAIN RESULTS: S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. CONCLUSIONS: Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.


Assuntos
Inflamação/etiologia , Monócitos/fisiologia , Proteínas S100/fisiologia , Sepse/imunologia , Receptor 4 Toll-Like/fisiologia , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas S100/sangue , Proteína S100A12 , Sepse/sangue , Receptor 4 Toll-Like/sangue , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA