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1.
Isr Med Assoc J ; 21(7): 487-490, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507126

RESUMO

BACKGROUND: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Pericardite/fisiopatologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Antígenos HLA/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Pericardite/genética , Pericardite/imunologia , Recidiva
2.
Int J Immunogenet ; 46(4): 232-240, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31135083

RESUMO

Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype-phenotype association of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The "variant detection rate in index patients" was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype-phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype-phenotype relationship, all PFS-related genes should be analysed together and the possibility of polygenic inheritance should be considered.


Assuntos
Febre Familiar do Mediterrâneo/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Éxons , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/patologia , Feminino , Febre/genética , Febre/imunologia , Febre/patologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Mutação , Pirina/genética
3.
Int J Mol Sci ; 20(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999610

RESUMO

Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)ß that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients' quality of life. IL-1ß blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1ß antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Artrite Juvenil/imunologia , Síndromes Periódicas Associadas à Criopirina/imunologia , Febre Familiar do Mediterrâneo/imunologia , Febre/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Interleucina-1beta/imunologia , Deficiência de Mevalonato Quinase/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Receptores de Interleucina-1/antagonistas & inibidores
4.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
5.
Scand J Rheumatol ; 48(4): 315-319, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30786810

RESUMO

Background: Chronic inflammation, as determined by persistently elevated acute-phase reactants in attack-free periods, can occasionally be observed in patients with familial Mediterranean fever (FMF) and is suggested to be a risk factor for the development of amyloidosis. We aimed to investigate the underlying causes of chronic inflammation in FMF patients and its association with amyloidosis in long-term follow-up. Method: Electronic medical records of FMF patients who had regular follow-up for ≥ 5 years in our cohort were utilized. As part of routine evaluation, detailed history, physical examination, and pertinent laboratory and radiographic investigations were performed in all patients to determine potential causes of elevated C-reactive protein (CRP) levels. Results: The study included 146 FMF patients who had no evidence of amyloidosis at baseline and had regular follow-up for ≥ 5 years. Thirty-seven patients (25.3%) were found to have chronic inflammation in the disease course. Twenty-five (67.5%) of them had either very frequent attacks or chronic manifestations of disease. In the entire study group, amyloidosis developed in five patients (3.42%) during the 5 year follow-up, four in the FMF with chronic inflammation group (10.8%), and only one of the 109 patients without chronic inflammation (odds ratio 13.09, 95% confidence interval 1.41-121.2). Conclusions: The results suggest that persistently high CRP levels during the attack-free periods may be a strong risk factor for the development of amyloidosis in patients with FMF. The vast majority of FMF patients with chronic inflammation had active FMF.


Assuntos
Proteínas da Fase Aguda/imunologia , Amiloidose , Febre Familiar do Mediterrâneo , Inflamação/sangue , Adulto , Amiloidose/diagnóstico , Amiloidose/etiologia , Amiloidose/imunologia , Proteína C-Reativa/análise , Registros Eletrônicos de Saúde/estatística & dados numéricos , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Seguimentos , Humanos , Masculino , Monitorização Fisiológica/métodos , Monitorização Fisiológica/estatística & dados numéricos , Medição de Risco , Fatores de Risco
6.
Mod Rheumatol ; 29(2): 363-366, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29578360

RESUMO

BACKGROUND: Colchicine is the mainstay of the treatment of familial Mediterranean fever (FMF). However, 10% of FMF patients do not respond well to colchicine. Efficacy of interleukin (IL)-1 inhibitors in reducing attacks have been demonstrated in colchicine-resistant FMF (crFMF) patients recently. Colchicine is still the only approved drug for the prevention of amyloidosis in FMF and utility of IL-1 inhibitors in crFMF cases who already has amyloidosis remain to be elucidated. Herein, we evaluated efficacy and safety of IL-1 inhibitors in patients with crFMF-associated AA amyloidosis in a relatively large single center study. METHODS: Medical records of FMF patients complicated with AA amyloidosis in our dedicated FMF center were retrospectively reviewed and those patients who ever treated with IL-1 inhibitors were enrolled into the study. Patient global, physician global assessments (on 0-10 cm visual analog scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine and 24-h urinary protein excretion values for each visit were recruited from computer-based hospital records. Treatment response of patients were assessed with clinical symptoms, serum albumin, CRP and ESR values. Renal outcome parameters were analyzed on those not receiving renal replacement therapy. RESULTS: Seventeen patients were identified with crFMF-amyloidosis that ever treated with IL-1 inhibitors. Background colchicine therapy was continued in all patients in maximal-tolerated dose along with IL-1 inhibitors. All patients benefit from IL-1 antagonists assessed by patient and physician global assessments. Inflammatory markers, CRP and ESR, were significantly reduced in all and normalized in 12 out of 17 patients. More importantly, the amount of proteinuria was remarkably improved following IL-1 inhibitor therapy (1606 mg/day to 519 mg/day, p = .008). Both anakinra and canakinumab were well-tolerated without severe side effects. All patients were initially treated with anakinra but switched to canakinumab in seven patients (one leukopenia, four injection site reaction, two inefficacy). CONCLUSION: We evaluated the clinical and laboratory responses to IL-1 inhibitors in crFMF-associated amyloidosis patients. We found significant decreases in CRP, ESR and proteinuria after IL-1 inhibitor therapy. This study confirmed that IL-1 inhibitors are effective for controlling attacks and inflammatory activity in FMF patients complicated with AA amyloidosis. Moreover, they reduce or stabilize amount of proteinuria and preserve renal function in short-term follow-up. Prolonged prospective clinical trials are warranted to assess their long-term efficacy in this particular patient group.


Assuntos
Amiloidose , Anticorpos Monoclonais , Colchicina , Febre Familiar do Mediterrâneo , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/antagonistas & inibidores , Adulto , Amiloidose/diagnóstico , Amiloidose/tratamento farmacológico , Amiloidose/epidemiologia , Amiloidose/etiologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Sedimentação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Colchicina/administração & dosagem , Colchicina/efeitos adversos , Monitoramento de Medicamentos/métodos , Resistência a Medicamentos , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteinúria/diagnóstico , Proteinúria/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Turquia/epidemiologia
7.
Clin Exp Rheumatol ; 36(6 Suppl 115): 116-124, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30582517

RESUMO

Familial Mediterranean fever (FMF), the most common of the systemic autoinflammatory disorders, is caused by mutations in the MEFV (Mediterranean Fever) gene, which encodes the protein pyrin. Neutrophils, one of the major components during inflammation, are the main cell type that expresses pyrin. In response to an inflammatory stimulus, neutrophils migration to their main active site. To date, several pyrin-interacting proteins have been demonstrated to co-localise with the cytoskeletal protein actin, which is important in the process of neutrophil migration and raises the question of whether pyrin plays a role in the actin cytoskeletal network during inflammatory cell migration. In this study, we examined the possible role of pyrin during inflammatory cell migration in neutrophils. We generated a cell migration assay with neutrophils and primary neutrophils from patients. We also knocked down pyrin expression using siRNA and then performed cell migration assay. We showed co-localisation of pyrin and F-actin at the leading edge during inflammatory cell migration. In pyrin knocked down cells, we identified a significant decrease in neutrophil migration. In addition, we demonstrated a dramatic increase in migration in the neutrophils of FMF patients compared with a healthy control group. These data together provide new insight into the cellular function of pyrin and demonstrate an important link between pyrin and polymerising actin in the process of inflammatory cell migration.


Assuntos
Quimiotaxia de Leucócito , Febre Familiar do Mediterrâneo/genética , Mutação , Neutrófilos/metabolismo , Pirina/genética , Pirina/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/metabolismo , Feminino , Predisposição Genética para Doença , Células HL-60 , Humanos , Masculino , Neutrófilos/imunologia , Fenótipo , Transdução de Sinais
8.
Rheumatology (Oxford) ; 57(1): 100-111, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040788

RESUMO

Objectives: FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli. Methods: IL-1ß and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time. Results: Monocytes from FMF patients secreted significantly more IL-1ß and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus. Conclusion: Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Febre Familiar do Mediterrâneo/genética , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pirina/genética , Trifosfato de Adenosina/farmacologia , Adolescente , Adulto , Antígenos de Bactérias/farmacologia , Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/farmacologia , Estudos de Casos e Controles , Morte Celular , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/imunologia , Feminino , Voluntários Saudáveis , Humanos , Inflamassomos/genética , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Ionóforos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Mutação , Nigericina/farmacologia , Pirina/imunologia , Salmonella typhimurium , Proteínas rho de Ligação ao GTP
9.
Eur J Immunol ; 48(2): 230-238, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29148036

RESUMO

Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogen- or host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.


Assuntos
Febre Familiar do Mediterrâneo/imunologia , Inflamassomos/metabolismo , Pirina/genética , Síndrome de Sweet/imunologia , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Febre Familiar do Mediterrâneo/genética , Homeostase , Humanos , Piroptose , Síndrome de Sweet/genética
10.
Int J Rheum Dis ; 21(10): 1873-1877, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24661635

RESUMO

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder that usually develops before 20 years of age and is characterized by periodic fever with serositis and arthritis. Both FMF and rheumatoid arthritis (RA) involve arthritis; however, their coexistence is rare. We describe two RA patients with an MEFV mutation in exon 2, who were diagnosed with FMF at an age of over 50 years. We also discuss the possibility that MEFV mutations could modulate RA disease activity.


Assuntos
Artrite Reumatoide/imunologia , Febre Familiar do Mediterrâneo/genética , Mutação , Pirina/genética , Idade de Início , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Fenótipo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Best Pract Res Clin Rheumatol ; 32(5): 651-661, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203923

RESUMO

AIM: To study the role of Toll-like receptor (TLR) 2 in Familial Mediterranean fever (FMF) inflammatory process. METHODS: TLR2 expression on monocytes of FMF attack-free patients (n = 20) and the effect of sera of FMF patients with an acute attack (n = 9) on TLR2 expression on monocytes of healthy donors were studied by flow cytometry (FACS). TLR2 expression was also studied in THP-1 cells, and TLR2 downstream signaling was studied by ELISA for the secretion of IL-1ß and pro-inflammatory cytokines or by western blotting to measure nuclear factor (NF)-κB. RESULTS: FMF attack-free patients had increased CD14 + TLR2+ cell count as compared to healthy donors. High-dose colchicine treatment (≥2 mg/d) inhibited this increased expression in FMF patients. Colchicine in vitro also inhibited TLR2 expression on THP-1 cells. Sera from FMF patients with an acute attack induced TLR2 expression by both monocytes of healthy donors and THP-1 cells as well as pro-inflammatory cytokine secretion by healthy monocytes, while colchicine inhibited this induction. Pam2CSK4 increased interleukin-1ß (IL-1ß) secretion by peripheral blood mononuclear cells (PBMCs) of healthy donors, and this activation was inhibited by colchicine. THP-1 cells presented elevated NF-κB expression when cultured with Pam2CSK4, whereas colchicine inhibited this elevation. CONCLUSIONS: TLR2 activation was upregulated in monocytes of FMF patients, and colchicine inhibited this upregulation both in -vitro and in -vivo. This indicates that elevated expression of TLR2 promotes the production of pro-inflammatory cytokines, which may contribute to uncontrolled inflammation in FMF.


Assuntos
Colchicina/farmacologia , Febre Familiar do Mediterrâneo/imunologia , Monócitos/efeitos dos fármacos , Receptor 2 Toll-Like/biossíntese , Humanos , Inflamação/imunologia , Monócitos/imunologia , Receptor 2 Toll-Like/análise , Moduladores de Tubulina/farmacologia , Regulação para Cima
13.
Ter Arkh ; 90(3): 38-41, 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-30701854

RESUMO

AIM: Determination of the concentration of interleukin-10 (IL-10) and interleukin-6 (IL-6) in serum of patients with periodic disease (PD) before and after treatment with colchicin, as well as the identification of correlation between the indicators of these parameters. MATERIALS AND METHODS: We examined 188 patients with PD (89 men, 99 women) aged from 12 to 69 years, as well as 44 patients with rheumatoid arthritis (RA) as a comparison group and 41 healthy people of the control group. Patients were divided into groups: 1 - PD colchicinotherapy patients with seizures without amyloidosis that do not respond to treatment maximum dose of colchicine 2.0 mg/day; 2nd-PD patients without amyloidosis, not responding to treatment 1.5 mg/day colchicine; 3rd - PD patients that responds to certain doses of colchicine (0.5 to 2.0 mg/day); 4th - PD patients without amyloidosis who did not receive treatment; 5-I of the healthy persons of the control group; 6-I - RA patients. The concentration of IL-10 in blood serum was determined by enzyme immunoassay ELISA, and IL-6 - immunochemiluminescent method. For statistical processing the computer program SPSS is used. The results were considered statistically significant at the level of reliability p<0.05. RESULTS: The results of the studies showed the same nature of changes in IL-10 production in different groups of patients. Statistically significant positive correlation of elevated serum concentrations of IL-6 and IL-10 (p<0.05) was found in patients with PD of all groups, as well as in patients with RA. CONCLUSION: In patients with PD (both colchicin-resistant and colchicin-sensitive) increased serum concentration of IL-10 was accompanied by an increased level of IL-6 in serum. Changes in the level of IL-10 in PD have a certain prognostic and pathogenetic significance and lead to the development of "persistent, sluggish" inflammatory process in the extracurricular period of PD in both colchicin-resistant and other groups of patients with PD.


Assuntos
Artrite Reumatoide , Febre Familiar do Mediterrâneo , Interleucina-10 , Interleucina-6 , Adolescente , Adulto , Idoso , Criança , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/imunologia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
14.
Allergol. immunopatol ; 45(6): 549-552, nov.-dic. 2017. tab
Artigo em Inglês | IBECS | ID: ibc-168462

RESUMO

Introduction: There are only a few studies regarding the prevalence of atopy in Familial Mediterranean fever (FMF) patients, and their results are conflicting. Methods: In this study children with the diagnosis of FMF were evaluated for the presence of atopy by comparing with controls. One hundred and eighteen children diagnosed as FMF and 50 healthy age and sex matched controls were enrolled. They were evaluated for the presence of rhinitis, atopic dermatitis, urticaria and asthma. Laboratory assessment was done by measuring IgA, IgM, IgG, IgE levels, total eosinophil count and by performing skin prick test (SPT) panels for common allergens to children with FMF and healthy controls. Results: One hundred and eighteen children (61girls and 57 boys) diagnosed as FMF with a median age of 120 ± 47 months (range 36-204 months) were compared with 50 healthy controls (31 girls and 19 boys) having a median age of 126±37 (range 48-192 months). The mean percentage of total eosinophil count of patients was similar to that of the control group. The mean level of IgE was significantly higher in children with FMF than controls (136 ± 268, 87 ± 201, respectively; p values < 0.05). The percentage of skin prick test positivity was similar for both patients and controls (13% and 8.2%, respectively; p > 0.05). The prevalences of atopic dermatitis, allergic rhinitis, and asthma in the patient group were 5.08%, 28.8%, and 15.25%, respectively, while the control group had the prevalences of 0%, 36%, and 14% respectively. Conclusion: Children with FMF did not show an increase of atopic dermatitis, allergic rhinitis and asthma with respect to controls (AU)


No disponible


Assuntos
Humanos , Febre Familiar do Mediterrâneo/imunologia , Hipersensibilidade Imediata/imunologia , Estudos de Casos e Controles , Biomarcadores/análise , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Asma/imunologia , Eczema/imunologia , Rinite Alérgica/imunologia , Estudos Prospectivos
15.
Clin Exp Rheumatol ; 35 Suppl 108(6): 75-81, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29148404

RESUMO

OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF". METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings. RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B. CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.


Assuntos
Febre Familiar do Mediterrâneo/genética , Febre/genética , Doenças Hereditárias Autoinflamatórias/genética , Heterozigoto , Homozigoto , Deficiência de Mevalonato Quinase/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/imunologia , Feminino , Febre/diagnóstico , Febre/epidemiologia , Febre/imunologia , Predisposição Genética para Doença , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/epidemiologia , Doenças Hereditárias Autoinflamatórias/imunologia , Hereditariedade , Humanos , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/epidemiologia , Deficiência de Mevalonato Quinase/imunologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prevalência , Pirina/genética , Fatores de Risco , Turquia/epidemiologia , Adulto Jovem
16.
PLoS One ; 12(8): e0182967, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28800602

RESUMO

OBJECTIVE: The aim of the current study was to determine the contributions of several common mutations in the Mediterranean fever (MEFV) gene, namely, E148Q, M680I, M694V and V726A, to ankylosing spondylitis (AS) susceptibility. METHODS: Two investigators independently searched the literature regarding the association of MEFV with AS in the PubMed, EMBASE, Web of Science, and Scopus databases. They independently selected eligible articles and then extracted data from the included studies. The associations between MEFV mutations and AS risk were assessed with odds ratios (ORs) and 95% confidence intervals (95% CI). Further analyses were conducted with STATA 12.0 software (Stata Corp.; College Station, Texas, USA). RESULTS: Four mutations (E148Q, M680I, M694V and V726A) were genotyped in 869 AS cases and 879 controls from the 8 eligible studies. Of the four mutations, M694V (pooled OR: 3.330, 95% CI: 2.129-5.208) was found to be associated with AS through overall analysis. However, the other mutations demonstrated no relation with AS (pooled ORs: 1.295, 1.258, 1.778; 95% CI: 0.886-1.891, 0.688-2.298 and 0.938-3.371). No significant publication bias was discovered in the meta-analysis. CONCLUSIONS: The present study indicates that the MEFV M694V mutation may contribute to the pathogenesis of AS. The associations between the other mutations and AS need to be validated with more relevant and well-designed studies.


Assuntos
Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença , Mutação , Pirina/genética , Espondilite Anquilosante/genética , Adulto , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Expressão Gênica , Humanos , Masculino , Razão de Chances , Pirina/imunologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia
17.
J Allergy Clin Immunol ; 140(5): 1378-1387.e13, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28342915

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is an IL-1ß-dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress. OBJECTIVE: We investigated the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1ß-bearing neutrophil extracellular traps (NETs) in patients with FMF. METHODS: RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase-DNA complex ELISA, and flow cytometry. Samples from patients with Still's disease and bacterial infections were used also. RESULTS: The stress-related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy-mediated NET release, which can be overcome through REDD1 induction. Stress-related mediators (eg, epinephrine) decrease this threshold, leading to autophagy-driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1ß and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL-1ß levels on NETs. CONCLUSIONS: This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL-1ß, and might constitute an important piece in the IL-1ß-mediated inflammation puzzle.


Assuntos
Febre Familiar do Mediterrâneo/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/metabolismo , Adulto , Autofagia , Progressão da Doença , Armadilhas Extracelulares/metabolismo , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Interleucina-1beta/metabolismo , Masculino , Pirina/genética , Remissão Espontânea , Estresse Fisiológico/imunologia , Adulto Jovem
18.
Exp Clin Transplant ; 15(Suppl 1): 240-243, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28260476

RESUMO

OBJECTIVES: We evaluated long-term results and infections requiring hospitalization in kidney transplant patients with Familial Mediterranean Fever (associated amyloidosis-type). MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with familial Mediterranean fever with at least 1-year posttransplant follow-up. Kidney transplant recipients with primary glomerulonephritis and equivalent demography, immunity status, and follow-up comprised the control group. RESULTS: In 32 patients with familial Mediterranean fever versus 25 control patients (mean follow-up 82 ± 57 vs 79 ± 54 mo; P = .82), average serum creatinine values were 1.7 ± 0.9 versus 1.5 ± 1.0 mg/dL (P = .41) at discharge, 1.4 ± 0.4 versus 1.3 ± 0.5 mg/dL (P = .44) at 1 year, 1.4 ± 0.6 versus 1.3 ± 0.5 mg/dL (P = .63) at 3 years, and 2.0 ± 1.5 versus 2.1 ± 1.5 mg/dL (P = .92) at last follow-up. Groups were not statistically different regarding average inpatient and number of hospitalizations due to infections at 1 year; however, at last follow-up, 26 patients with familial Mediterranean fever (81%) had 8.6 average admissions and 13 control patients (52%) had 2.8 average admissions (P = .02, P < .01). Early posttransplant, both groups were taking a triple drug immunosuppression regimen. However, at 1 and 3 years posttransplant, withdrawal and/or minimization occurred in 40.6% and 83.3% of patients with familial Mediterranean fever and 28% and 55.5% of control patients (P < .05, P < .05). During follow-up, 6 familial Mediterranean fever patients (18.7%) and 2 control patients (8%) died (P = .23). CONCLUSIONS: Although renal transplant patients with associated amyloidosis-type familial Mediterranean fever and those with glomerulonephritis have similar rejection and/or graft loss rates, hospital admissions due to infection and increased mortality are more common in the familial Mediterranean fever group, with immunosuppression drug withdrawal.


Assuntos
Doenças Transmissíveis/etiologia , Febre Familiar do Mediterrâneo/complicações , Transplante de Rim/efeitos adversos , Insuficiência Renal/cirurgia , Adulto , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/mortalidade , Doenças Transmissíveis/terapia , Substituição de Medicamentos , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/mortalidade , Feminino , Hospitalização , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Registros Médicos , Pessoa de Meia-Idade , Insuficiência Renal/etiologia , Insuficiência Renal/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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