RESUMO
BACKGROUND: Pulmonary arterial hypertension consists in an increase of mean pulmonary arterial pressure (PAPm ≥ 25 mmHg), and may lead to right ventricular failure. Pulmonary arterial hypertension can arise in several disorders, encompassing inflammatory conditions and connective tissue diseases. The occurrence of pulmonary arterial hypertension has recently been reported in monogenic interferonopathies and in systemic lupus erythematosus, highlighting the pathogenic role of type I interferons and paving the way to therapies aimed at inhibiting interferon signaling. CASE: We describe a 17-year-old boy with DNase II deficiency, presenting a clinical picture with significant overlap with systemic lupus erythematosus. During treatment with the Janus kinase inhibitor ruxolitinib, he developed pulmonary arterial hypertension, raising the question whether it could represent a sign of insufficient disease control or a drug-related adverse event. The disease even worsened after drug withdrawal, but rapidly improved after starting the drug again at higher dosage. SUMMARY AND CONCLUSION: Pulmonary arterial hypertension can complicate type I interferonopathies. We propose that ruxolitinib was beneficial in this case, but the wider role of Janus kinase inhibitors for the treatment of pulmonary arterial hypertension is not clear. For this reason, a strict cardiologic evaluation must be part of the standard care of subjects with interferonopathies, especially when Janus kinase inhibitors are prescribed.
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By GWAS studies on celiac disease, gene expression was studied at the level of the whole intestinal mucosa, composed by two different compartments: epithelium and lamina propria. Our aim is to analyse the gene-expression and DNA methylation of candidate genes in each of these compartments. Epithelium was separated from lamina propria in biopsies of CeD patients and CTRs using magnetic beads. Gene-expression was analysed by RT-PC; methylation analysis required bisulfite conversion and NGS. Reverse modulation of gene-expression and methylation in the same cellular compartment was observed for the IL21 and SH2B3 genes in CeD patients relative to CTRs. Bioinformatics analysis highlighted the regulatory elements in the genomic region of SH2B3 that altered methylation levels. The cREL and TNFAIP3 genes showed methylation patterns that were significantly different between CeD patients and CTRs. In CeD, the genes linked to inflammatory processes are up-regulated, whereas the genes involved in the cell adhesion/integrity of the intestinal barrier are down-regulated. These findings suggest a correlation between gene-expression and methylation profile for the IL21 and SH2B3 genes. We identified a "gene-expression phenotype" of CeD and showed that the abnormal response to dietary antigens in CeD might be related not to abnormalities of gene structure but to the regulation of molecular pathways.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença Celíaca/patologia , Metilação de DNA , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Interleucinas/genética , Adolescente , Biópsia , Doença Celíaca/genética , Criança , Pré-Escolar , Duodeno/química , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Mucosa Intestinal/química , Masculino , Proteínas Proto-Oncogênicas c-ret/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To assess the predictive value of sonographic cervical-length (CL) measurement in mid-gestation for spontaneous preterm birth (PTB) in asymptomatic triplet pregnancy. METHODS: This was a retrospective study of asymptomatic triplet pregnancies followed at five Italian tertiary referral centers, between 2002 and 2015. CL was measured transvaginally between 18 and 24 weeks' gestation. Pregnancies with medically indicated PTB were excluded. Demographic and pregnancy characteristics of pregnancies complicated by PTB were analyzed and the distributions of CL measurements in these patients were calculated. Logistic regression analysis was performed to assess the association between CL and PTB, adjusted for confounders. Performance of CL measurement in prediction of PTB < 28, < 30 and < 32 weeks of gestation was assessed. RESULTS: A total of 120 triplet pregnancies were included in the final analysis. Median CL was 35 (interquartile range (IQR), 29-40) mm measured at a median gestational age of 20 + 2 (IQR, 20 + 0 to 23 + 4) weeks. Overall, 23 (19.2%), 17 (14.2%) and eight (6.7%) patients had a CL < 25, < 20 and < 15 mm, respectively. Spontaneous PTB < 32 weeks occurred in 41 (34.2%) cases, < 30 weeks in 23 (19.2%) and < 28 weeks in 12 (10%) cases. CL < 15 mm was significantly more frequent in the group of patients who delivered < 28 (P = 0.03) and < 30 (P = 0.01) weeks' gestation, compared with those who delivered after 28 and after 30 weeks, respectively, while CL < 20 mm was more common in triplet pregnancies with delivery < 32 weeks compared with those delivered ≥ 32 weeks (P = 0.03). Logistic regression analysis was possible only for PTB < 32 weeks due to the small number of cases that delivered < 30 and < 28 weeks. After adjustment for confounders, CL was not significantly associated with PTB < 32 weeks (adjusted odds ratio, 0.97; 95% CI, 0.94-1.01). CL measurement had an area under the receiver-operating characteristics curve of 0.41 (95% CI, 0.20-0.62), 0.41 (95% CI, 0.26-0.56) and 0.42 (95% CI, 0.31-0.54) for the prediction of spontaneous PTB < 28, < 30 and < 32 weeks, respectively. CONCLUSION: CL assessed in mid-gestation is a poor predictor of PTB < 28, < 30 and < 32 weeks' gestation in asymptomatic triplet pregnancy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Assuntos
Medida do Comprimento Cervical , Valor Preditivo dos Testes , Gravidez de Trigêmeos , Nascimento Prematuro/diagnóstico , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Estudos RetrospectivosRESUMO
Glucocorticoids (GCs) exert their effects through regulation of gene expression after activation in the cytoplasm of the glucocorticoid receptor (GR) encoded by NR3C1 gene. A negative feedback mechanism resulting in GR autoregulation has been demonstrated through the binding of the activated receptor to intragenic sequences called GRE-like elements, contained in GR gene. The long noncoding RNA growth arrest-specific transcript 5 (GAS5) interacts with the activated GR suppressing its transcriptional activity. The aim of this study was to evaluate the possible role of GAS5 and NR3C1 gene expression in the antiproliferative effect of methylprednisolone in peripheral blood mononuclear cells and to correlate the expression with individual sensitivity to GCs. Subjects being poor responders to GCs presented higher levels of GAS5 and NR3C1 in comparison with good responders. We suggest that abnormal levels of GAS5 may alter GC effectiveness, probably interfering with the mechanism of GR autoregulation.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , RNA Longo não Codificante/biossíntese , Receptores de Glucocorticoides/biossíntese , Adulto , Proliferação de Células/efeitos dos fármacos , Feminino , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Receptores de Glucocorticoides/genética , Transcrição GênicaRESUMO
Mevalonate Kinase Deficiency (MKD) is an autosomal-recessively inherited disorder of cholesterol biosynthesis with higher prevalence in the Netherlands and other North European countries. MKD is due to mutations in the second enzyme of mevalonate pathway (mevalonate kinase, MK/MVK) which results in reduced enzymatic activity and in the consequent shortage of downstream compounds. In most severe cases the deregulation of mevalonate pathway is associated with a decrease in serum cholesterol. More than 100 pathological mutations have been described in the MVK gene so far, and a founder effect has been hypothesized as responsible for the diffusion of the most frequent disease-associated mutations. In the acute phase of disease, patients affected with MKD present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals. Low cholesterol levels are widely known to correlate with the reduction of cardiovascular events. We hypothesize a selective advantage for heterozygote carriers of the most frequent MVK mutations in those countries where the diet is characterized by high consumption of saturated animal fats rich in cholesterol. This could explain the maintenance in North European population of the main mutations leading to MKD and the distribution world-wide of these mutations that followed the migrations of North European populations.
Assuntos
Evolução Biológica , Predisposição Genética para Doença/genética , Deficiência de Mevalonato Quinase/epidemiologia , Deficiência de Mevalonato Quinase/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Seleção Genética , Colesterol/sangue , Dieta Hiperlipídica , Europa (Continente)/epidemiologia , Genes Recessivos/genética , Humanos , Modelos Biológicos , Mutação/genéticaRESUMO
Phylloid hypomelanosis is a distinct type of pigmentary mosaicism characterized by congenital hypochromic macules resembling a floral ornament with various elements such as round or oval patches, asymmetrical macules similar to begonia leaves, or oblong lesions. It has been found to be predominantly associated with abnormalities in chromosome 13 and sometimes as-sociated with different extracutaneous abnormalities. Here, we report 2 new cases of phylloid hypomelanosis due to mosaicism involving chromosome 13. The first one is a mosaicism for a supernumerary marker belonging to chromosome 13 and the second one is the first report of phylloid hypomelanosis associated with a mosaic deletion of 13q. Because of the extremely low level of mosaicism in these 2 cases, SNP array analysis on skin fibroblasts was carried out, showing a 13q21.33-q34 duplication (71,024,411-115,103,529) and a 13q13.3-q34 (38,368,012-115,103,529) deletion. Both cases underline on the one hand the strict connection between phylloid hypomelanosis and anomalies of chromosome 13, and on the other hand the relevance of the SNP array analysis on skin fibroblasts in the detection of low-level mosaicism.
Assuntos
Cromossomos Humanos Par 13/genética , Hipopigmentação/diagnóstico , Mosaicismo , Polimorfismo de Nucleotídeo Único , Humanos , Hipopigmentação/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodosRESUMO
OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.
Assuntos
Febre Familiar do Mediterrâneo/genética , Febre/genética , Linfadenite/genética , Mutação/genética , Faringite/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/fisiologia , Adolescente , Antirreumáticos/uso terapêutico , Terapia Biológica , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/fisiopatologia , Feminino , Febre/tratamento farmacológico , Febre/fisiopatologia , Seguimentos , Genótipo , Inquéritos Epidemiológicos , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Estudos Longitudinais , Linfadenite/tratamento farmacológico , Linfadenite/fisiopatologia , Masculino , Faringite/tratamento farmacológico , Faringite/fisiopatologia , Qualidade de Vida , Recidiva , Estudos Retrospectivos , Esteroides/uso terapêutico , SíndromeRESUMO
OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.
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Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Índice de Gravidade de Doença , Adolescente , Adulto , Fatores Etários , Idoso , Algoritmos , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Diarreia/etiologia , Humanos , Lactente , Pessoa de Meia-Idade , Dor/etiologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pirina , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Sensibilidade e Especificidade , Estomatite Aftosa/etiologiaRESUMO
The generation of regulatory T cells (Tregs) in vitro represents an attractive possibility to set up cellular therapies that could prevent and cure autoimmune disorders. Different methods have been proposed to generate Tregs in vitro and to evaluate their phenotype and function. Moreover, the overlap between generation of activated and regulatory cells could often be underestimated. We showed that in vitro treatment of CD4+ CD25- lymphocytes with different stimuli leads to a good expression of CD25 and forkhead box P3 (FoxP3) on most cells, but to a full Treg phenotype (including CD127 negativity) in only a minor percentage of cells, ranging from 17.38% of cells treated with phytohaemagglutinin (PHA) to 50.91% of cells treated with T cell receptor (TCR) stimulation in association with transforming growth factor (TGF)-beta. Some suppressive activity was demonstrated for T cells activated with all the different stimuli. However, while suppression mediated by TCR/TGF-beta treated T cells was associated with an inhibition of both interleukin (IL)-2 and interferon (IFN)-gamma in the co-culture supernatant, the suppression observed for PHA-activated cells occurred in the presence of large amounts of these cytokines. In conclusion, also taking into account other recent publications, caution should be taken in interpretation of data in the field of regulatory T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Interferon gama/biossíntese , Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Fito-Hemaglutininas/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
OBJECTIVE: We report the experience of the Italian Registry of patients affected by chronic infantile neurological, cutaneous, articular (CINCA) syndrome. The clinical and genetic features of 12 unrelated Italian patients with CINCA syndrome are described, focusing on the possible influence of the presence of CIAS1/cryopyrin mutations on the phenotype of the disease and on its prognosis. METHODS: The clinical features of 12 Italian CINCA patients were evaluated. Genomic DNA of the patients was sequenced using specific primers for CIAS1 and ASC genes. RESULTS: Our patients shared typical CINCA characteristics and, sometimes, remarkable perinatal events, peculiar of CIAS1-mutated patients. Seven patients carried CIAS1 missense mutation, localized within the nucleotide binding domain of cryopyrin. Four previously described mutations and three new heterozygous CIAS1 missense mutations were identified. ASC gene, encoding for a direct interactor of cryopyrin, was not mutated in Italian CINCA patients. Finally, we reported the efficacy and safety of anti-IL1 therapy (Anakinra) in seven patients with a particularly severe CINCA phenotype. CONCLUSION: Despite some common signs-used as syndrome hallmarks-we observed a high variability in symptoms, genetic results and outcomes in Italian CINCA patients. In contrast with other authors, we cannot find out any correlation between mutations in CIAS1 and CINCA severity, but we underlined the concomitance of perinatal events and mental retardation only in CIAS1 mutated subjects. Finally, we confirmed the efficacy of Anakinra treatment, both in CIAS1-mutated and non-mutated patients.
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Artrite/diagnóstico , Proteínas de Transporte/genética , Inflamação/diagnóstico , Adolescente , Adulto , Artrite/tratamento farmacológico , Artrite/genética , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Avaliação de Medicamentos , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sistema de Registros , Síndrome , Resultado do Tratamento , Urticária/diagnóstico , Urticária/tratamento farmacológico , Urticária/genéticaRESUMO
AIMS: To determine coeliac disease prevalence by an anti-transglutaminase antibody assay in a large paediatric population; to evaluate acceptance of the screening programme, dietary compliance, and long term health effects. METHODS: Cross-sectional survey of 3188 schoolchildren (aged 6-12) and prospective follow up of diagnosed cases. Main outcome measures were: prevalence of coeliac disease defined by intestinal biopsy or positivity to both human tissue transglutaminase and anti-endomysium antibodies in HLA DQ2-8 positive subjects; percentage of children whose families accepted screening; dietary compliance as defined by negativity for anti-transglutaminase antibodies; and presence of clinical or laboratory abnormalities at 24 month follow up. RESULTS: The families of 3188/3665 children gave their consent (87%). Thirty biopsy proven coeliacs were identified (prevalence 1:106). Three other children testing positive for both coeliac related autoantibodies and HLA DQ2-8 but refusing biopsy were considered as having coeliac disease (prevalence 1:96). Of 33 cases, 12 had coeliac related symptoms. The 30 biopsy proven coeliacs followed a gluten-free diet. Of 28 subjects completing 18-24 months follow up, 20 (71.4%) were negative for anti-transglutaminase antibodies, while eight were slightly positive; symptoms resolved in all 12 symptomatic children. CONCLUSIONS: Prevalence of coeliac disease is high in Italian schoolchildren. Two thirds of cases were asymptomatic. Acceptance of the programme was good, as was dietary compliance. Given the high prevalence and possible complications of untreated coeliac disease, the availability of a valid screening method, and evidence of willingness to comply with dietary treatment population mass screening deserves careful consideration.
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Anticorpos/sangue , Doença Celíaca/diagnóstico , Programas de Rastreamento/métodos , Transglutaminases/imunologia , Doença Celíaca/epidemiologia , Criança , Estudos Transversais , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Itália/epidemiologia , Masculino , Cooperação do Paciente , Estudos Prospectivos , Transglutaminases/sangueAssuntos
Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Gliadina/imunologia , Imunoglobulina A/sangue , Transglutaminases/imunologia , Adulto , Doadores de Sangue , Doença Celíaca/sangue , Doença Celíaca/epidemiologia , Análise Custo-Benefício , Erros de Diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Prevalência , Estados Unidos/epidemiologiaAssuntos
Febre Familiar do Mediterrâneo/tratamento farmacológico , Hipergamaglobulinemia/tratamento farmacológico , Imunoglobulina D/sangue , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Receptores do Fator de Necrose Tumoral/administração & dosagem , Pré-Escolar , Etanercepte , Febre Familiar do Mediterrâneo/complicações , Humanos , Hipergamaglobulinemia/complicações , Masculino , Falha de TratamentoRESUMO
OBJECTIVE: The aims of the study were to assess the effect of intra-articular treatment with triamcinolone hexacetonide (TH) in juvenile idiopathic arthritis (JIA) and to investigate whether treatment response correlates with the presence of antinuclear antibodies (ANA) in the serum and/or B CD5+ and T gamma/delta + lymphocytes in the synovial fluid. METHODS: A total of 37 patients (81% females, 56% ANA+) with oligoarticular JIA involving knees were treated with intra-articular injections of TH after failing to respond to NSAIDs for two months. Eighteen patients were treated within 6 months of onset, 19 were treated more than 6 months after onset. RESULT: Mean duration of remission was 13.9 months. Twelve patients (7 ANA+) had stable remission after a single injection; 13 patients (3 ANA+) experienced more than 6 months' remission but subsequently had a relapse; 12 patients (11 ANA+) had a relapse within six months of injection. Of 20 patients treated within 6 months of onset, 17 had stable remission whereas only 8 out of 17 who were treated during relapse attained stable remission (p = 0.03). The mean percentage of T gamma/delta + and of B CD5+ lymphocytes in synovial fluid was the same as in peripheral blood of normal subjects. CONCLUSION: Our data indicate that local treatment with slow-release steroids is very effective in oligoarticular JIA. Prolonged remission was less likely in the presence of ANA positivity, probably because the disease is immunologically more active. Finally, our data suggest that the earlier the treatment, the easier it is to obtain a protracted, and possibly permanent, response.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Antinucleares/sangue , Artrite Juvenil/tratamento farmacológico , Subpopulações de Linfócitos B/metabolismo , Articulação do Joelho , Líquido Sinovial/metabolismo , Subpopulações de Linfócitos T/metabolismo , Triancinolona Acetonida/análogos & derivados , Triancinolona Acetonida/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Artrite Juvenil/imunologia , Subpopulações de Linfócitos B/imunologia , Antígenos CD5 , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intra-Articulares , Masculino , Estudos Prospectivos , Resultado do Tratamento , Triancinolona Acetonida/administração & dosagemRESUMO
Immune dysregulation, polyendocrinopathy and enteropathy with X-linked inheritance (IPEX) is a serious disease arising from mutations in FOXP3. This gene codifies for a transcription factor whose dysfunction results in hyperactivation of T cells. It is not clear, however, why an intermediate phenotype is not seen in heterozygous females, who are completely healthy. In order to address this question, we investigated X-chromosome inactivation in peripheral blood lymphocytes from a heterozygous female with a child affected by IPEX. No preferential inactivation was shown in freshly sorted CD4+, CD8+, CD19+ cells or in IL-2 cultured CD4 and CD8 T cells, indicating that peripheral blood lymphocytes in these women are randomly selected. Moreover, only one single FOXP3 transcript was expressed by CD4 T cell clones analysed by RT-PCR, confirming that this gene is subject to X- inactivation. We hypothesize that hyper-activation of T cell in carriers of FOXP3 mutations is regulated by the presence of normal regulatory T cells.
Assuntos
Proteínas de Ligação a DNA/genética , Mecanismo Genético de Compensação de Dose , Doenças do Sistema Endócrino/genética , Subpopulações de Linfócitos/patologia , Transtornos Linfoproliferativos/genética , Adulto , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/fisiologia , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Feminino , Fatores de Transcrição Forkhead , Genótipo , Heterozigoto , Humanos , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Masculino , Mutação de Sentido Incorreto , Mutação Puntual , SíndromeRESUMO
Celiac disease (CD) is frequently associated with an autoimmune disorder (AD). The aim of the study was to establish if an AD is more frequent than expected in relatives of CD patients and, in particular, if it is related to the presence of silent unrecognised CD. We also evaluated the prevalence of ADs in CD patients and compared it with that in a control series. A structured questionnaire was used to evaluate the prevalence of ADs in 125 (51 males and 74 females with a mean age of 8.9 years) children with CD (group A), 125 (67 males and 58 females with a mean age of 8.1 years) matched "healthy" children (group B), all 1352 first- and second-degree relatives of the 125 children with CD (group C), all 1238 first- and second-degree relatives of the control group B of "healthy" children (group D), and all 205 first- and second-degree relatives of 20 children with AD (group E). We also used the antiendomysium antibody assay to screen 354 of the 373 first-degree relatives of group C. An AD was present in 9 of the 125 (7.2%) children with CD (group A), in 1 of the 125 (0.8%) healthy children (group B), in 67 of the 1352 (4.9%) relatives of CD patients (group C), in 14 of the 1238 (1.1%) relatives of healthy children (group D), and in 7 of the 205 (3.4%) of relatives of patients with AD (group E). Clinically silent CD was found in 20 of the 354 first-degree relatives of CD patients (5.6%), and the risk of silent CD was significantly higher, reaching 25% (4/16) in the subgroup of relatives also affected by another AD. Relatives of CD patients had an increased prevalence of AD compared to control groups, and relatives of CD patients with ADs, have a risk as high as 25% of being silent celiacs: they should thus be screened for CD.
Assuntos
Doenças Autoimunes/genética , Doença Celíaca/complicações , Adulto , Anticorpos/análise , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Criança , Feminino , Humanos , Masculino , PrevalênciaRESUMO
We describe a 10-month-old boy diagnosed with X-linked hyper-IgM syndrome (XHIM) after suffering from life-threatening acute respiratory distress syndrome (ARDS) caused by Pneumocystis carinii pneumonia (PCP), although his previous clinical history and first level laboratory tests investigating immunological function did not indicate immunodeficiency. When the patient's overall condition was good, elective bone marrow transplantation from an HLA-matched older brother was performed successfully. We describe how correct diagnosis and successful treatment were made possible thanks to the involvement of a network of specialists.
Assuntos
Transplante de Medula Óssea , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Hipergamaglobulinemia/terapia , Imunoglobulina M/sangue , Ligante de CD40/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/diagnóstico , Lactente , Masculino , Pneumonia por Pneumocystis/etiologia , Síndrome , Linfócitos T/imunologia , Transplante HomólogoRESUMO
BACKGROUND: The main autoantigen recognized by the sera of patients with coeliac disease (CD) is tissue transglutaminase (tTG). A human-recombinant form of tTG was used to develop an ELISA to measure anti-tTG serum antibodies for the diagnosis of CD. Preliminary retrospective reports suggest that the human tTG-based ELISA could identify coeliac patients missed by the IgA-anti-endomysium antibody test (AEA). Whether the human recombinant tTG ELISA is sufficiently accurate to become the main diagnostic CD tool in everyday clinical practice is unknown. The objective was to determine, in a prospective study, the sensitivity and specificity of an ELISA test based on the use of human tTG compared with AEA, to analyse the discordant cases for HLA DQ2-8 and for clinical and intestinal biopsy characteristics. METHODS: 1106 patients referred to a gastrointestinal outpatient clinic for symptoms attributable to CD, 52 first-degree relatives of CD patients and 200 healthy controls were tested for both anti-human tTG and AEA antibodies. RESULTS: Out of 1158 subjects, 146 were tested positive for anti-tTG antibodies and 140 were biopsy-proven coeliacs. The AEA test identified 126/1158 coeliacs who also tested positive for anti-tTG antibodies. The 14 patients missed by the AEA test carried the typical HLA-DQ for CD; they had normal levels of total serum IgA and had milder pathology than those with both anti-tTG and AEA positivity (P < 0001). CONCLUSIONS: These results prove that human tTG-based ELISA is an excellent diagnostic tool for CD, for mass screening by both the specialist and the general clinic.
Assuntos
Autoanticorpos/análise , Doença Celíaca/diagnóstico , Ensaio de Imunoadsorção Enzimática , Transglutaminases/sangue , Adolescente , Adulto , Idoso , Instituições de Assistência Ambulatorial , Biópsia por Agulha , Estudos de Casos e Controles , Doença Celíaca/epidemiologia , Criança , Pré-Escolar , Feminino , Mucosa Gástrica/patologia , Antígenos HLA-DQ/análise , Humanos , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Probabilidade , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Transglutaminases/análiseRESUMO
Celiac disease (CD) is an intestinal malabsorption characterized by intolerance to cereal proteins accompanied by immunological responses to dietary gliadins and tissue transglutaminase, an autoantigen located in the endomysium. Tissue transglutaminase belongs to the family of enzymes that catalyze protein cross-linking reactions and is constitutively expressed in many tissues as well as being activated during apoptosis. The role of gliadins in eliciting the immune response in CD and how transglutaminase is linked to the primary reaction are still unclear. In this work, we report the production and analysis of six phage Ab libraries from the peripheral and intestinal lymphocytes of three CD patients. We were able to isolate Abs to transglutaminase from all intestinal lymphocytes libraries but not from those obtained from peripheral lymphocytes. This is in contrast to Abs against gliadin, which could be obtained from all libraries, indicating that the humoral response against transglutaminase occurs at the local level, whereas that against gliadin occurs both peripherally and centrally. Abs from all three patients recognized the same transglutaminase epitopes with a bias toward the use of the V(H)5 Ab variable region family. The possible role of these anti-transglutaminase Abs in the onset of CD and associated autoimmune pathologies is discussed.