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ABSTRACT: OBJECTIVES: To define in patients affected by familial Mediterranean fever (FMF) whether or not interleukin (IL)-1β secretion (1) is enhanced, (2) correlates with the type of MEFV mutation and (3) is mediated by NLRP3. METHODS: Freshly isolated monocytes from 21 patients with FMF (12 homozygous and 9 heterozygous), 14 MEFV healthy carriers and 30 healthy donors (HDs), unstimulated or after lipopolysaccharide (LPS)-induced activation, were analysed for redox state (production of reactive oxygen species (ROS) and antioxidant responses) and IL-1β and IL-1 receptor antagonist (IL-1Ra) secretion. NLRP3 down-modulation was induced by in vitro silencing of the NLRP3 gene. RESULTS: LPS-stimulated monocytes from patients with FMF displayed enhanced IL-1β secretion, which correlated with number and penetrance of MEFV mutations. Silencing of NLRP3 consistently inhibited IL-1β secretion. As in other autoinflammatory diseases, FMF monocytes produced more ROS than genetically negative cells from HDs. Unlike in cryopyrin-associated periodic fever syndromes (CAPS), however, they were characterised by a conserved and sustained antioxidant response. Consistent with this finding, activated MEFV-mutated monocytes did not exhibit the functional indicators of oxidative stress observed in CAPS, including accelerated IL-1β secretion and deficient production of IL-1Ra. CONCLUSIONS: MEFV-mutated monocytes display enhanced IL-1β secretion, which correlates with number of high-penetrance mutations and level of endogenous ROS. Unlike NLRP3-mutated cells, monocytes carrying MEFV mutations withstand oxidative stress and preserve IL-1Ra production, thereby limiting inflammation. Finally, in contrast with that found in the animal model, the increased secretion of IL-1β by LPS-stimulated FMF monocytes is NLRP3-dependent.
Annals of the rheumatic diseases 03/2013; · 8.11 Impact Factor
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Rheumatology (Oxford, England) 03/2013; · 4.24 Impact Factor
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Seza Ozen,
Erkan Demirkaya,
Gayane Amaryan,
Isabelle Koné-Paut,
Adem Polat,
Pat Woo,
Yosef Uziel,
Consuelo Modesto,
Martina Finetti,
Pierre Quartier, [......],
Luca Cantarini,
Joost Frenkel,
Susan Nielsen,
Michael Hofer,
Antonella Insalaco,
C Acikel,
Huri Ozdogan,
Alberto Martini,
Nicolino Ruperto, Marco Gattorno
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ABSTRACT: BACKGROUND AND AIM: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. METHODS: Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. RESULTS: Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. CONCLUSIONS: Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.
Annals of the rheumatic diseases 03/2013; · 8.11 Impact Factor
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Giuliana Cangemi,
Angela Pistorio,
Maurizio Miano, Marco Gattorno,
Maura Acquila,
Maria Patrizia Bicocchi,
Roberto Gastaldi,
Francesca Riccardi,
Cinzia Gatti,
Francesca Fioredda,
Michaela Calvillo,
Giovanni Melioli,
Alberto Martini,
Carlo Dufour
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ABSTRACT: OBJECTIVES: Hepcidin, a peptide hormone released by hepatocytes into circulation is the main regulator of dietary iron absorption and cellular iron release. Although commercial tests are available, assay harmonization for hepcidin has not been yet reached, making reference intervals and consequent clinical decisions still elusive for each assay and specific population. The aim of this study is to set up hepcidin measurement in pediatric age and to investigate its potential usefulness in the diagnosis and management of iron disorders in children. METHODS: Serum hepcidin was measured by using an automated commercial immunoassay. Reference values were obtained from 86 healthy children. Hepcidin was then evaluated in 52 children with diseases where this hormone was expected to be differently regulated. RESULTS: Hepcidin values were 43.6 ng/mL median; 32-52.7 1-3 q: in males and 36.4 ng/mL median; 28.5-45.7 1-3 q: in females (P = 0.039). Hepcidin was significantly higher in postpubertal normal females than in normal males. Hepcidin resulted up-regulated in anemia of chronic disease of children affected by systemic Juvenile Idiopathic Arthritis and decreased after treatment with anakinra, an anti-interleukin-1 receptor antagonist. In iron deficiency anemia patients on oral iron supplementation and in β-thalassemia subjects, hepcidin levels were similar to those found in healthy subjects. CONCLUSIONS: This study sets up reference values for pediatric population and shows that in normal controls serum hepcidin react differently to puberty in females vs. males. In addition, it suggests that serum hepcidin may discriminate microcytic inflammatory anemia of Juvenile Idiopathic Arthritis from iron deficiency anemia. Overall these findings may represent a helpful tool for future studies tailored to understand the role of hepcidin in management of iron disorders in children.
European Journal Of Haematology 02/2013; · 2.61 Impact Factor
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Roberta Caorsi,
Loredana Lepore,
Francesco Zulian,
Maria Alessio,
Achille Stabile,
Antonella Insalaco,
Martina Finetti,
Antonella Battagliese,
Giorgia Martini,
Chiara Bibalo,
Alberto Martini, Marco Gattorno
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ABSTRACT: INTRODUCTION: Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data is available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype. METHODS: 13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation. RESULTS: 7 patients with Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, 4 patients with as Muckle-Wells syndrome (MWS) and 2 patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced an higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab. CONCLUSIONS: The use of canakinumab in daily practice is associated with a persistent satisfactory control of disease activity but needs a progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.
Arthritis research & therapy 02/2013; 15(1):R33. · 4.27 Impact Factor
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Arthritis & Rheumatism 02/2013; · 7.87 Impact Factor
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Nicoletta Solari,
Elena Palmisani,
Alessandro Consolaro,
Angela Pistorio,
Stefania Viola,
Antonella Buoncompagni, Marco Gattorno,
Paolo Picco,
Nicolino Ruperto,
Clara Malattia,
Alberto Martini,
Angelo Ravelli
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ABSTRACT: OBJECTIVE: To evaluate the rate of inactive disease in children with juvenile idiopathic arthritis (JIA) treated with etanercept, and to identify clinical characteristics associated with attainment of inactive disease. METHODS: Clinical charts of patients who were given etanercept between January 2002 and January 2011 were evaluated retrospectively. For each patient, all visits from initiation of etanercept to the last followup evaluation in which the patient was still receiving etanercept were examined to establish whether the patient had reached the state of inactive disease and to identify the first visit in which inactive disease was documented. Clinical characteristics associated with achievement of inactive disease were determined through univariate analyses and Cox regression procedures. RESULTS: A total of 173 patients who received etanercept for a median of 2.2 years (range 0.5-10.5 yrs) were studied. Eighty-seven patients (50.3%) achieved inactive disease after a median of 0.6 years (range 0.1-2.5 yrs) of therapy. At last followup evaluation, 85 patients (49.1%) still had inactive disease and 70 (40.5%) were in clinical remission on medication. The probability of achievement of inactive disease after 6, 12, and 24 months of therapy was 24%, 46% and 57%, respectively. On Cox regression analysis, the attainment of inactive disease was associated with lack of wrist involvement and an age at disease onset < 3.6 years. CONCLUSION: Around half of our patients with JIA treated with etanercept achieved a state of inactive disease. Children who lacked wrist involvement and were younger at disease onset had a greater likelihood of achieving inactive disease.
The Journal of Rheumatology 12/2012; · 3.69 Impact Factor
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Tiziana Bachetti,
Sabrina Chiesa,
Patrizio Castagnola,
Daniele Bani,
Eleonora Di Zanni,
Alessia Omenetti,
Andrea D'Osualdo,
Alessandro Fraldi,
Andrea Ballabio,
Roberto Ravazzolo,
Alberto Martini, Marco Gattorno,
Isabella Ceccherini
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ABSTRACT: OBJECTIVES: Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. METHODS: The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. RESULTS: We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. CONCLUSIONS: Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.
Annals of the rheumatic diseases 10/2012; · 8.11 Impact Factor
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Marco Gattorno,
Alessandra Piccini,
Denise Lasigliè,
Sara Tassi,
Giacomo Brisca,
Sonia Carta,
Laura Delfino,
Francesca Ferlito,
Maria Antonietta Pelagatti,
Francesco Caroli,
Antonella Buoncompagni,
Stefania Viola,
Anna Loy,
Marina Sironi,
Annunciata Vecchi,
Angelo Ravelli,
Alberto Martini,
Anna Rubartelli
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ABSTRACT: PURPOSE OF THE REVIEW: Inherited autoinflammatory syndromes are conditions caused by mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to an uncontrolled inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review we give a start of the art of the use of biologics in these disorders. MAIN TOPICS: The dramatic response to anti IL-1 drugs in cryopyrin-associated periodic syndromes represents the brightest example of the possibility to completely dampen inflammation in these severe disorders with the selective blockade of a single pivotal cytokine. Periodic fevers are characterized by recurrent episodes of fever, usually treated with on demand steroids. However the increasing frequency of fever episodes or the development of a chronic disease course may require a continuous long-term treatment, with anti-TNF or IL-1 blockers in mevalonate kinase deficiency and TNF-receptor associated periodic syndrome. Anti-IL-1 treatment is also effective in FMF patients resistant or partially responsive to colchicine. The deficiency of the interleukin-1-receptor antagonist (DIRA) is caused by mutations in the gene encoding for the interleukin-1 receptor antagonist (IL-1Ra). In this case t he recombinant IL-1Ra (anakinra) is the treatment of choice. Due to their extreme rarity the response to the available biologic drugs in other autoinflammatory diseases is still largely anecdotal.
Autoimmunity reviews 08/2012; 12(1):81-6. · 6.37 Impact Factor
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Nienke Ter Haar,
Helen Lachmann,
Seza Ozen,
Pat Woo,
Yosef Uziel,
Consuelo Modesto,
Isabelle Koné-Paut,
Luca Cantarini,
Antonella Insalaco,
Bénédicte Neven, [......],
Silvana Martino,
Jasmin Kuemmerle-Deschner,
Laura Obici,
Nicolae Iagaru,
Anna Simon,
Susan Nielsen,
Alberto Martini,
Nicolino Ruperto, Marco Gattorno,
Joost Frenkel
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ABSTRACT: OBJECTIVE: To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. METHODS: The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. RESULTS: 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. CONCLUSIONS: In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.
Annals of the rheumatic diseases 06/2012; · 8.11 Impact Factor
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ABSTRACT: To determine whether dysregulated production of cytokines downstream of interleukin (IL)-1 participates in the pathophysiology of cryopyrin-associated periodic syndromes (CAPS).
Primary monocytes from patients with CAPS, unstimulated or after stimulation with lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists, were examined for signs of stress and production of IL-1β, IL-1 receptor antagonist (IL-1Ra) and IL-6 in comparison with monocytes from patients with autoimmune diseases and from healthy donors.
Unstimulated CAPS monocytes showed mild signs of stress including elevated levels of reactive oxygen species and fragmented mitochondria. Stress signs were worsened by TLR stimulation and eventually led to protein synthesis inhibition with strong impairment of production of cytokines downstream of IL-1, such as IL-1Ra and IL-6. These defects were not detected in monocytes from autoimmune patients and healthy donors.
The stress state of LPS-stimulated CAPS monocytes and the consequent inhibition of translation are likely to be responsible for the impaired production of IL-1Ra and IL-6. The deficient secretion of these cytokines coupled with increased IL-1β release explains the severity of the IL-1-related clinical manifestations and the predominant implication of innate immunity in CAPS.
Annals of the rheumatic diseases 06/2012; 71(9):1577-81. · 8.11 Impact Factor
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ABSTRACT: Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to few families and share the capability of sensing pathogen-associated and damage-associated molecular patterns. By interacting with each other, these proteins participate in the assembling of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory gene or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a robust model to study these mechanisms and possibly to develop new classes of anti-inflammatory drugs.
Current pharmaceutical design 06/2012; · 4.41 Impact Factor
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Silvia Federici,
Giuseppina Calcagno,
Martina Finetti,
Romina Gallizzi,
Antonella Meini,
Agata Vitale,
Francesco Caroli,
Marco Cattalini,
Roberta Caorsi,
Francesco Zulian,
Alberto Tommasini,
Antonella Insalaco,
Maria Pia Sormani,
Maurizia Baldi,
Isabella Ceccherini,
Alberto Martini, Marco Gattorno
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ABSTRACT: OBJECTIVE: To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever.METHODS: 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients.RESULTS: Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of 'familial Mediterranean fever (FMF)-like symptoms' decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for 'periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms'.CONCLUSIONS: This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.
Annals of the rheumatic diseases 05/2012; · 8.11 Impact Factor
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ABSTRACT: Autoinflammatory diseases are a group of diseases characterized by inflammatory attacks. The monogenic forms of these diseases
are also classified as the hereditary periodic fever syndromes. All are characterized by attacks of fever along with certain
clinical features and high acute phase reactants. Most of these monogenic diseases are associated with hereditary disorders
of the interleukin-1 pathway. The most common autoinflammatory disease is familial Mediterranean fever. The other rather common
monogenic diseases are the tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinemia D with periodic
fever syndrome, and cryopyrin-associated periodic fever syndromes (CAPS). However, a number of multifactorial diseases such
as Behçet disease are now also categorized under the topic of autoinflammatory diseases. The main features and management
of these diseases will be reviewed. Finally, we introduce the “Eurofever” project, aimed to increase awareness and education
for the aforementioned diseases. We conclude that the pediatrician should be aware of the features and management of autoinflammatory
diseases since all present with fever—the most common symptom of pediatric practice.
KeywordsAutoinflammatory diseases–Familial Mediterranean fever–Tumor necrosis factor receptor-associated periodic syndrome–Hyperimmunoglobulinemia D with periodic fever syndrome–Cryopyrin-associated periodic fever syndromes
European Journal of Pediatrics 04/2012; 170(4):445-452. · 1.88 Impact Factor
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Nataša Toplak,
Pavla Dolezalovà,
Tamas Constantin,
Anna Sedivà,
Srdjan Pašić,
Peter Čižnar,
Beata Wolska-Kuśnierz,
Miroslav Harjaček,
Mariana Stefan,
Nicolino Ruperto, Marco Gattorno,
Tadej Avčin
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ABSTRACT: ObjectiveTo analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries,
with a particular interest on the diagnostic facilities in these countries.
MethodsTwo different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever
survey and collection of data with the structured questionnaire.
ResultsData from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed
familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated
periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly
higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF
patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients.
ConclusionsThe number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify
more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases
and to establish a network for genetic testing of periodic fever syndromes in ECE countries.
Pediatric Rheumatology 04/2012; 8(1):1-5. · 1.44 Impact Factor
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ABSTRACT: The immune system consists of 2 branches: innate and adaptive. The former represents the first line of host defense during infection and plays a key role in the early recognition and protection against invading pathogens. The latter orchestrates elimination of pathogens in the late phase of infection and leads to the generation of immunologic memory. Innate and adaptive immunity should not be considered separate compartments. Innate and adaptive immune responses represent an integrated system of host defense. The authors review the mechanisms driving the induction and perpetuation of the inflammatory responses observed during pathogen-associated, autoimmune, and autoinflammatory diseases.
Pediatric Clinics of North America 04/2012; 59(2):225-43. · 2.24 Impact Factor
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ABSTRACT: IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity. However, the requirements for differentiation and the properties of pathogen-induced human TH17 cells remain poorly defined. Using an approach that combines the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, we describe here two types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific TH17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1β contributed to TH17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-γ double-producing cells. In addition, IL-1β inhibited IL-10 production in differentiating and in memory TH17 cells, whereas blockade of IL-1β in vivo led to increased IL-10 production by memory TH17 cells. We also show that, after restimulation, TH17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-γt. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime TH17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro- and anti-inflammatory regulators of TH17 cells both at priming and in the effector phase.
Nature 04/2012; 484(7395):514-8. · 36.28 Impact Factor
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Natasa Toplak,
Joost Frenkel,
Seza Ozen,
Helen J Lachmann,
Patricia Woo,
Isabelle Koné-Paut,
Fabrizio De Benedetti,
Benedicte Neven,
Michael Hofer,
Pavla Dolezalova, [......],
Herman Girschick,
Carlos Rose,
Carine Wouters,
Richard Vesely,
Juan Arostegui,
Silvia Stojanov,
Huri Ozgodan,
Alberto Martini,
Nicolino Ruperto, Marco Gattorno
[show abstract]
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ABSTRACT: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project.
A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms.
1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997.
A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.
Annals of the rheumatic diseases 02/2012; 71(7):1177-82. · 8.11 Impact Factor
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Archives of Disease in Childhood 02/2012; 97(6):561-3. · 2.88 Impact Factor
