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1.
Sci Rep ; 12(1): 15206, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076017

RESUMO

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term 'origin score' to capture the dose and different combinations of the grandparents' origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.


Assuntos
Febre Familiar do Mediterrâneo , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/genética , Humanos , Israel , Judeus , Aprendizado de Máquina , Mutação , Pirina/genética
2.
Int J Mol Sci ; 23(18)2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36142364

RESUMO

Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1ß, IL-1α, and IL-18 and induce a type of inflammatory cell death known as "pyroptosis". Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions.


Assuntos
Inflamassomos , Piroptose , Caspase 3 , Caspases/metabolismo , Inflamassomos/metabolismo , Interleucina-18 , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina
3.
Turk J Pediatr ; 64(4): 781-786, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082654

RESUMO

BACKGROUND: Amyloidosis is a group of disorders with extracellular accumulation of autologous fibrillary insoluble proteins in various tissues and organs such as the kidneys, liver, spleen, heart and gastrointestinal tract leading to impairment of normal organ function. Childhood amyloidosis is an exceedingly rare entity mainly caused by familial Mediterranean fever (FMF) and the other autoinflammatory diseases such as mevalonate kinase deficiency (MKD). CASE: A 16-year-old male was referred to pediatric nephrology for coincidentally discovered proteinuria. He had no significant findings on physical examination except for urochromic color. He had nephrotic range proteinuria with 109 mg/m2/h and serum creatinine was 1.35 mg/dl. Kidney biopsy was performed because of nephrotic range proteinuria with acute kidney injury. In hematoxylin-eosin-stained tissue sections, amyloid was suggested as extracellular amorphous material that is lightly eosinophilic in the glomeruli. Diagnosis was confirmed by Congo red positivity, with apple-green birefringence under polarized light. MEFV gene mutation was negative and a compound heterozygote mutation found in mevalonate kinase gene. A 6-monthtrial of colchicine, enalapril, and losartan combination was not successful; Canakinumab was started thereafter. Proteinuria and creatinine decreased to 7 mg/m2/h and 0.6 mg/dl respectively 4 years after treatment. CONCLUSIONS: Amyloidosis should be considered especially in children presenting with proteinuria and with a history of recurrent fever. This report also emphasizes the efficacy of canakinumab to prevent or decelerate chronic renal failure in these patients although it does not reduce tissue deposition in long-term use.


Assuntos
Injúria Renal Aguda , Amiloidose , Febre Familiar do Mediterrâneo , Adolescente , Amiloidose/complicações , Amiloidose/diagnóstico , Criança , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Humanos , Rim/patologia , Masculino , Proteinúria/etiologia , Pirina/genética , Proteína Amiloide A Sérica
5.
Oxid Med Cell Longev ; 2022: 3790721, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111168

RESUMO

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). However, the precise molecular mechanisms remain largely unclear, and it is still a challenging disease to diagnose and treat. The nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome is a critical part of the innate immune system in the host to defend against endogenous danger and pathogenic microbial infections. Dysregulated NLRP3 inflammasome activation results in the overproduction of cytokines, primarily IL-1ß and IL-18, and eventually, inflammatory cell death-pyroptosis. A series of studies have indicated that NLRP3 inflammasome activation participates in the development of DCM, and that corresponding interventions could mitigate disease progression. Accordingly, this narrative review is aimed at briefly summarizing the cell-specific role of the NLRP3 inflammasome in DCM and provides novel insights into developing DCM therapeutic strategies targeting the NLRP3 inflammasome.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Humanos , Inflamassomos , Interleucina-18 , Leucina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nucleotídeos , Pirina
6.
Pediatr Rheumatol Online J ; 20(1): 72, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045426

RESUMO

BACKGROUND: During childhood, the most common periodic fever is periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The effective treatment and prevention of febrile attacks improve these patients' and their families' quality of life. However, there is no single strategy or evidence-based guideline to manage this syndrome, and most of them are based on consensus treatment plans. METHODS: This randomized controlled trial was carried out on 67 PFAPA patients referred to three tertiary centers of pediatric rheumatology. The patients were divided into two groups, including group 1 (n = 36) receiving prednisolone plus colchicine and group 2 (n = 31) receiving prednisolone plus cimetidine. Demographic characteristics and the number of febrile episodes were compared between the two groups before and after the intervention. RESULTS: In both groups, the number of febrile episodes after the treatment decreased (P ≤ 0.001). Statistical Analysis showed no significant difference between the two groups (P = 0.88). Moreover, 44 patients from both groups were checked for the MEFV gene. There were no statistical differences between MEFV positive and negative subgroups in response to colchicine (P = 1). CONCLUSION: This study showed that both drug regimens are significantly effective in preventing febrile attacks in PFAPA syndrome, and the presence of a MEFV gene mutation might not be the only significant risk factor for a response to colchicine. TRIAL REGISTRATION: IRCT, IRCT20191222045847N1. Registered 23 October 2019, https://fa.irct.ir/search/result?query=IRCT20191222045847N1.


Assuntos
Linfadenite , Linfadenopatia , Faringite , Estomatite Aftosa , Criança , Cimetidina/uso terapêutico , Colchicina/uso terapêutico , Febre/tratamento farmacológico , Febre/prevenção & controle , Humanos , Linfadenite/tratamento farmacológico , Linfadenite/prevenção & controle , Mutação , Faringite/tratamento farmacológico , Faringite/prevenção & controle , Prednisolona/uso terapêutico , Pirina/genética , Qualidade de Vida , Estomatite Aftosa/tratamento farmacológico , Estomatite Aftosa/genética , Estomatite Aftosa/prevenção & controle , Síndrome
7.
Nutrients ; 14(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35956392

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by short acute attacks, with an as yet unknown cause. Several authors have investigated the role of some foods as potential triggers. This narrative review aims to analyze the correlation between diet and FMF clinical outcomes. METHODS: The review was carried out following PRISMA statement guidelines, including all cross-sectional, case-crossover, and trial studies written in English and conducted between 1974 and 2022. RESULTS: Overall, 642 records were identified through PubMed/MEDLINE (292) and Scopus (350), and seven studies were included: three out of seven (43%) studies evaluated FMF attack recurrence or time between consumption of high-fat foods and FMF attacks, while another three (43%) articles variously assessed FMF severity, and one (14%) evaluated the distribution of MEFV mutations. CONCLUSIONS: To date, conflicting results have been reported about fatty and salty food intake and FMF attack recurrence. Moreover, some authors have suggested a possible role of wheat. Finally, a diet rich in antioxidants and supplements with an anti-inflammatory effect could partially reduce symptoms and improve the well-being of FMF patients. Nevertheless, no conclusive data could be drawn about the impact of diet in FMF symptom triggering, and further studies are required to clarify this putative association.


Assuntos
Febre Familiar do Mediterrâneo , Estudos Transversais , Dieta , Febre Familiar do Mediterrâneo/genética , Humanos , Mutação , Pirina/genética
8.
Inflammation ; 45(5): 1849-1863, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35953688

RESUMO

The novel coronavirus SARS-CoV-2, responsible for the COVID-19 outbreak, has become a pandemic threatening millions of lives worldwide. Recently, several vaccine candidates and drugs have shown promising effects in preventing or treating COVID-19, but due to the development of mutant strains through rapid viral evolution, urgent investigations are warranted in order to develop preventive measures and further improve current vaccine candidates. Positive-sense-single-stranded RNA viruses comprise many (re)emerging human pathogens that pose a public health problem. Our innate immune system and, in particular, the interferon response form an important first line of defense against these viruses. Flexibility in the genome aids the virus to develop multiple strategies to evade the innate immune response and efficiently promotes their replication and infective capacity. This review will focus on the innate immune response to SARS-CoV-2 infection and the virus' evasion of the innate immune system by escaping recognition or inhibiting the production of an antiviral state. Since interferons have been implicated in inflammatory diseases and immunopathology along with their protective role in infection, antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin-domain-containing 3 (NLRP3) inflammasome pathway, and release of its products including the pro-inflammatory cytokines IL-6, IL-18, and IL-1ß. This predictive view may aid in designing an immune intervention or preventive vaccine for COVID-19 in the near future.


Assuntos
COVID-19 , Inflamassomos , Antivirais , Vacinas contra COVID-19 , Humanos , Imunidade Inata , Inflamassomos/metabolismo , Interferons , Interleucina-18 , Interleucina-6 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina , SARS-CoV-2
10.
BMC Genom Data ; 23(1): 60, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35909123

RESUMO

BACKGROUND: Bladder cancer has the characteristics of high morbidity and mortality, and the prevalence of bladder cancer has been increasing in recent years. Immune and autophagy related genes play important roles in cancer, but there are few studies on their effects on the prognosis of bladder cancer patients. METHODS: Using gene expression data from the TCGA-BLCA database, we clustered bladder cancer samples into 6 immune-related and autophagy-related molecular subtypes with different prognostic outcomes based on 2208 immune-related and autophagy-related genes. Six subtypes were divided into two groups which had significantly different prognosis. Differential expression analysis was used to explore genes closely related to the progression of bladder cancer. Then we used Cox stepwise regression to define a combination of gene expression levels and immune infiltration indexes to construct the risk model. Finally, we built a Nomogram which consist of risk score and several other prognosis-related clinical indicators. RESULTS: The risk model suggested that high expression of C5AR2, CSF3R, FBXW10, FCAR, GHR, OLR1, PGLYRP3, RASGRP4, S100A12 was associated with poor prognosis, while high expression level of CD96, IL10, MEFV pointed to a better prognosis. Validation by internal and external dataset suggested that our risk model had a high ability to discriminate between the outcomes of patients with bladder cancer. The immunohistochemical results basically confirmed our results. The C-Index value and Calibration curves verified the robustness of Nomogram. CONCLUSIONS: Our study constructed a model that included a risk score for patients with bladder cancer, which provided a lot of helps to predict the prognosis of patients with bladder cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária , Autofagia/genética , Humanos , Imunidade/genética , Nomogramas , Prognóstico , Pirina , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Fatores ras de Troca de Nucleotídeo Guanina
11.
BMJ Case Rep ; 15(7)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831068

RESUMO

Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterised by recurrent fever attacks and serositis. Chronic inflammatory seronegative arthropathy affects the spine and peripheral joints and rarely coexists with FMF. Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that manifests as an ulcerative skin disease that uncommonly occurs in patients with FMF. In this case report, we describe a male patient in his 60s with a history of FMF and chronic inflammatory seronegative arthropathy who developed ulcerative skin lesions consistent with PG. A genetic evaluation revealed a pathogenic variant (V726A) and two variants of uncertain significance (F479L and E167D) mutations in the MEFV gene. We hypothesised that the triad of FMF, chronic inflammatory seronegative arthropathy and PG might be linked to the V726A variant, while the presence of the other two variants may have amplified the clinical presentation. Further studies are warranted to confirm our observation.


Assuntos
Febre Familiar do Mediterrâneo , Artropatias , Pioderma Gangrenoso , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/genética , Humanos , Masculino , Mutação , Pioderma Gangrenoso/complicações , Pirina/genética
12.
Front Immunol ; 13: 917398, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812376

RESUMO

Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease that causes recurrent fever, arthritis, and serositis. The diagnosis of FMF is based on the presentation of typical clinical symptoms and the Mediterranean fever gene (MEFV) test. However, the challenge lies in diagnosing atypical cases. In this report, we have described a pediatric patient with complex FMF whose diagnosis required trio-whole exome sequencing (WES) and functional validation of a rare MEFV variant. A 3-year-old boy presented with recurrent episodes of elevated liver enzymes and arthralgia. He was diagnosed with autoimmune hepatitis (AIH), and his liver enzymes improved rapidly with steroid treatment. However, he exhibited recurrent arthralgia and severe abdominal attacks. Trio-WES identified compound heterozygous mutations in MEFV (V726A and I692del). Ex vivo functional assays of the patient's monocytes and macrophages, which had been pre-treated with Clostridium difficile toxin A (TcdA) and colchicine, were comparable to those of typical FMF patients, thereby confirming the diagnosis of FMF. Although he was intolerant to colchicine because of liver toxicity, subsequent administration of canakinumab successfully ameliorated his abdominal attacks. However, it was ineffective against liver injury, which recurred after steroid tapering. Therefore, in this case, the pathogenesis of AIH was probably interleukin-1ß (IL-1ß)-independent. In fact, AIH might have been a concurrent disease with FMF, rather than being one of its complications. Nevertheless, further studies are necessary to determine whether FMF-induced inflammasome activation contributes to AIH development. Moreover, we must consider the possibility of mixed phenotypes in such atypical patients who present distinct pathologies simultaneously.


Assuntos
Febre Familiar do Mediterrâneo , Hepatite Autoimune , Artralgia , Criança , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Humanos , Masculino , Mutação , Pirina/genética
13.
Front Immunol ; 13: 921253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812440

RESUMO

Hereditary periodic recurrent fevers (HRF) are monogenic autoinflammatory associated to mutations of some genes, such as diseases caused by mutations of including MEFV, TNFRSF1A and MVK genes. Despite the identification of the causative genes, the intracellular implications related to each gene variant are still largely unknown. A large -scale proteomic analysis on monocytes of these patients is aimed to identify with an unbiased approach the mean proteins and molecular interaction networks involved in the pathogenesis of these conditions. Monocytes from HRF 15 patients (5 with MFV, 5 TNFRSF1A and 5with MVK gene mutation) and 15 healthy donors (HDs) were analyzed by liquid chromatography and tandem mass spectrometry before and after lipopolysaccharide (LPS) stimulation. Significant proteins were analyzed through a Cytoscape analysis using the ClueGo app to identify molecular interaction networks. Protein networks for each HRF were performed through a STRING database analysis integrated with a DISEAE database query. About 5000 proteins for each HRF were identified. LPS treatment maximizes differences between up-regulated proteins in monocytes of HRF patients and HDs, independently from the disease's activity and ongoing treatments. Proteins significantly modulated in monocytes of the different HRF allowed creating a disease-specific proteomic signatures and interactive protein network. Proteomic analysis is able to dissect the different intracellular pathways involved in the inflammatory response of circulating monocytes in HRF patients. The present data may help to identify a "monocyte proteomic signature" for each condition and unravel new possible unexplored intracellular pathways possibly involved in their pathogenesis. These data will be also useful to identify possible differences and similarities between the different HRFs and some multifactorial recurrent fevers.


Assuntos
Doenças Hereditárias Autoinflamatórias , Monócitos , Febre , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Lipopolissacarídeos/metabolismo , Monócitos/metabolismo , Proteômica , Pirina/metabolismo
14.
Semin Arthritis Rheum ; 56: 152055, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35780723

RESUMO

OBJECTIVE: To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. METHODS: Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. RESULTS: The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype. CONCLUSION: Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.


Assuntos
Doenças Autoimunes , Dosagem de Genes , Pirina , Doenças Autoimunes/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Mutação , Pirina/genética , Estudos Retrospectivos
15.
Methods Mol Biol ; 2523: 179-195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35759198

RESUMO

The pyrin inflammasome detects effectors and toxins that inhibit RhoA GTPases and triggers inflammatory cytokines release and a fast cell death termed pyroptosis. Ancient plague pandemics in the Mediterranean basin have selected in the human population pyrin variants that can trigger an autoinflammatory disease termed familial Mediterranean fever (FMF). In addition, distinct mutations in MEFV, the gene encoding pyrin, cause a different rare autoinflammatory disease termed pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). As of today, more than 385 MEFV variants have been described although for most of them, whether they are pathogenic variant or benign polymorphism is unknown.Here, we describe different methods using primary human monocytes or engineered monocytic cell lines to functionally characterize MEFV variants, determine their potential pathogenicity, and classify them as either FMF-like or PAAND-like variants.


Assuntos
Febre Familiar do Mediterrâneo , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Inflamassomos/metabolismo , Monócitos/metabolismo , Mutação , Pirina/genética , Piroptose
16.
BMC Pulm Med ; 22(1): 211, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643452

RESUMO

BACKGROUND: There is increasing evidence of small airway abnormalities in smokers despite normal spirometry. The concavity in the descending limb of the maximum expiratory flow curve (MEFV) is a recognised feature of obstruction and can provide information beyond FEV1, and potentially early smoking-related damage. We aimed to evaluate concavity measures compared to known small airway measurements. METHODS: Eighty smokers with normal spirometry had small airway function assessed: multiple breath nitrogen washout (MBNW) from which ventilation heterogeneity in the diffusion-dependent acinar (Sacin) and convection-dependent conductive (Scond) airways were assessed, and impulse oscillometry system (IOS) from which respiratory resistance and reactance at 5 Hz (R5 and X5) were measured. Concavity measures were calculated from the MEFV, partitioned into global and peripheral concavity. RESULTS: We found abnormal peripheral and global concavity as well as acinar ventilation heterogeneity are common in "normal" smokers. Concavity measures were not related to either MBNW or IOS measurements. CONCLUSION: Abnormalities in concavity indices and MBNW or oscillometry parameters are common in smokers despite normal spirometry. However, these measures likely reflect different mechanisms of peripheral airway dysfunction.


Assuntos
Pulmão , Fumantes , Humanos , Oscilometria , Pirina , Testes de Função Respiratória , Espirometria
17.
J Am Heart Assoc ; 11(11): e024931, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35658515

RESUMO

Background Idiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP. Methods and Results We retrospectively analyzed the medical records of patients with IRP (n=136) and monogenic autoinflammatory diseases (n=1910) attending a national center (London, UK) between 2000 and 2021. We examined 4 genes (MEFV, MVK, NLRP3, TNFRSF1A) by next-generation sequencing in 128 patients with IRP and compared the frequency of rare deleterious variants to controls obtained from the Genome Aggregation Database. In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain (adjusted odds ratio 2.8 [95% CI, 1.3-6.5], P=0.012). IRP frequently manifested with systemic inflammation (raised C-reactive protein [121/136, 89.0%] and extrapericardial effusions [68/136, 50.0%]). Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%-3.7% of cases). Rare deleterious MEFV variants were more frequent in IRP than in ancestry-matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040). Conclusions Pericarditis is a feature of interleukin-1 driven monogenic autoinflammatory diseases and IRP is associated with variants in MEFV, a gene involved in interleukin-1ß processing. We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain. Together these data implicate autoinflammation in IRP and support reducing reliance on corticosteroids in its management.


Assuntos
Doenças Hereditárias Autoinflamatórias , Pericardite , Corticosteroides , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Pericardite/diagnóstico , Pericardite/tratamento farmacológico , Pericardite/genética , Pirina/genética , Encaminhamento e Consulta , Estudos Retrospectivos
18.
J Immunother ; 45(6): 284-290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35621992

RESUMO

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.


Assuntos
Antineoplásicos Imunológicos , Melanoma , Segunda Neoplasia Primária , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/genética , Segunda Neoplasia Primária/etiologia , Pirina
19.
Int J Immunopathol Pharmacol ; 36: 3946320221104554, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35615856

RESUMO

INTRODUCTION: Dialysis-related amyloidosis (DRA) caused by ß2-microgloblin (B2M) fibrils is a serious complication for patients with kidney failure on long-term dialysis. Deposition of B2M amyloid fibrils is thought to be due not only to serum extracellular B2M but also to infiltrating inflammatory cells, which may have an important role in B2M amyloid deposition in osteoarticular tissues in patients with DRA. Here, we asked whether B2M amyloid fibrils activate the inflammasome and contribute to formation and deposition of amyloid fibrils in cells. METHODS: Amyloid formation was confirmed by a thioflavin T (ThT) spectroscopic assay and scanning electron microscopy (SEM). Activation of inflammasomes was assessed by detecting interleukin (IL)-1ß in culture supernatants from human embryonic kidney (HEK) 293T cells ectopically expressing inflammasome components. IL-1ß secretion was measured by enzyme-linked immunosorbent assay. Expression and co-localization were analyzed by immunohistochemistry and dual immunofluorescence microscopy. RESULTS: B2M amyloid fibrils interacted directly with NLRP3/Pyrin and to activate the NLRP3/Pyrin inflammasomes, resulting in IL-1ß secretion. When HEK293T cells were transfected with inflammasome components NLRP3 or Pyrin, along with ASC, pro-caspase-1, pro-IL-1ß, and B2M, ThT fluorescence intensity increased. This was accompanied by IL-1ß secretion, which increased in line with the amount of transfected B2M. In this case, morphological glowing of amyloid fibrils was observed by SEM. In the absence of ASC, there was no increase in ThT fluorescence intensity or IL-1ß secretion, or any morphological glowing of amyloid fibrils. NLRP3 or Pyrin and B2M were co-localized in a "speck" in HEK293T cells, and co-expressed in infiltrated monocytes/macrophages in the osteoarticular synovial tissues in a patient with DRA. CONCLUSION: Taken together, these data suggest that inflammasome assembly is required for the subsequent triggering of intracellular formation of B2M amyloid fibrils, which may contribute to osteoarticular deposition of B2M amyloid fibrils and inflammation in patients with DRA.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Amiloide , Células HEK293 , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina
20.
Oncology ; 100(7): 376-383, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35551132

RESUMO

INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.


Assuntos
Proteínas do Citoesqueleto , Neoplasias , Criança , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Células Germinativas , Humanos , Japão/epidemiologia , Mutação , Neoplasias/genética , Prognóstico , Pirina/genética
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