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2.
Clin Immunol ; 201: 15-19, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30742970

RESUMO

CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.


Assuntos
Síndromes de Imunodeficiência/genética , Subunidade alfa de Receptor de Interleucina-2/deficiência , Citocinas/imunologia , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Lactente , Subunidade alfa de Receptor de Interleucina-2/química , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Mutação , Conformação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/imunologia
3.
JMM Case Rep ; 5(10): e005167, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30479781

RESUMO

Introduction: LPS-responsive beige-like anchor (LRBA) protein deficiency is a disease of immune dysregulation with autoimmunity affecting various systems. Case Presentation: Two male siblings with a novel LRBA mutation had different primary findings at admission: the younger sibling had chronic early-onset diarrhoea and the elder one had autoimmune haemolytic anaemia. During long-term follow-up for IPEX phenotype, both developed hypogammaglobulinaemia, enteropathy and lung involvement. The patients partially responded to immunosuppressive therapies. A homozygous c.2496C>A, p.Cys832Ter (p.C832*) mutation in the LRBA gene causing a premature stop codon was detected. After molecular diagnosis, abatacept, as a target-specific molecule, was used with promising results. Conclusion: LRBA deficiency is a recently defined defect, with variable presentations in different patients; a single, definitive treatment option is thus not yet available.

4.
Front Immunol ; 9: 2411, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443250

RESUMO

Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.


Assuntos
Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Predisposição Genética para Doença , Enteropatias/diagnóstico , Enteropatias/genética , Fenótipo , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/etiologia , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Biomarcadores , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Heterogeneidade Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoglobulina E/imunologia , Estimativa de Kaplan-Meier , Masculino , Mutação , Poliendocrinopatias Autoimunes/mortalidade , Poliendocrinopatias Autoimunes/terapia , Síndrome , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
5.
J Allergy Clin Immunol ; 141(3): 1036-1049.e5, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241729

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário/congênito , Imunossupressão , Mutação , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Diarreia/mortalidade , Diarreia/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/terapia , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
6.
Curr Opin Allergy Clin Immunol ; 17(5): 317-324, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28817385

RESUMO

PURPOSE OF REVIEW: Immune dysregulation disorders present with common clinical features of multiorgan autoimmunity. Gastrointestinal involvement is the hallmark of an impaired immune homeostasis. This review will give an overview on the novel phenotypes, highlighting the major points that will help to enable early diagnosis and treatment. RECENT FINDINGS: The rapid progress on DNA sequencing technologies have led to the identification of monogenic defects that adversely impact the control of immune homeostasis. Lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Regulatory T cells (Tregs) play an essential role in enforcing immune tolerance. Here we illustrate disorders caused by impairment of mechanisms ensuring Tregs function (Tregs related) in which autoimmunity is a hallmark of the clinical disease presentation and other disorders, affecting molecules more broadly involved in immune responses and indirectly causing immune dysregulation (Tregs unrelated). Clinical presentation is sometime mischievous and often symptoms are analogous in different diseases and can mislead diagnosis. SUMMARY: The increasing comprehension of immunological concepts behind immune dysregulation diseases will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially as some patients might require hematopoietic stem cell transplantation.


Assuntos
Autoimunidade , Transplante de Células-Tronco Hematopoéticas , Tolerância Imunológica , Doenças Inflamatórias Intestinais/imunologia , Linfócitos T Reguladores/imunologia , Fatores Etários , Idade de Início , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Homeostase , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Terapia de Alvo Molecular
8.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
10.
Blood ; 128(2): 227-38, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27099149

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transativadores/imunologia
12.
Ital J Pediatr ; 40: 68, 2014 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-25326164

RESUMO

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.


Assuntos
Diarreia/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Poliendocrinopatias Autoimunes/complicações , Enteropatias Perdedoras de Proteínas/complicações , Linfócitos T Reguladores/imunologia , Criança , Diarreia/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Masculino , Mutação , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Enteropatias Perdedoras de Proteínas/genética , Enteropatias Perdedoras de Proteínas/imunologia , Síndrome
13.
J Clin Immunol ; 34(4): 398-424, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24619621

RESUMO

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Triagem Neonatal/estatística & dados numéricos , Infecções Oportunistas/prevenção & controle , Autoimunidade , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Diagnóstico Precoce , Expressão Gênica , Humanos , Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/terapia , Fatores Imunológicos/uso terapêutico , Recém-Nascido , Mutação , Triagem Neonatal/métodos , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
15.
Blood ; 123(6): 863-74, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24345756

RESUMO

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.


Assuntos
Linfócitos B/patologia , Células Dendríticas/patologia , Fator de Transcrição GATA2/genética , Células Matadoras Naturais/patologia , Monócitos/patologia , Mutação/genética , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Evolução Clonal , Estudos Transversais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Linhagem , Prognóstico , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/metabolismo
16.
Eur J Hum Genet ; 22(2): 197-201, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23756439

RESUMO

Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1.


Assuntos
Artropatia Neurogênica/genética , Coxa Vara/genética , Deformidades Congênitas da Mão/genética , Proteoglicanas/genética , Sinovite/genética , Adolescente , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Europa (Continente) , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Repetições de Microssatélites , Deleção de Sequência , Dissomia Uniparental
17.
J Allergy Clin Immunol ; 131(6): 1611-23, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23534974

RESUMO

BACKGROUND: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. OBJECTIVE: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. METHODS: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations. RESULTS: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation. CONCLUSIONS: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.


Assuntos
Fatores de Transcrição Forkhead/genética , Genes Dominantes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Enteropatias/genética , Mutação , Poliendocrinopatias Autoimunes/genética , Fator de Transcrição STAT1/genética , Adolescente , Autoanticorpos/imunologia , Linhagem Celular Transformada , Criança , Pré-Escolar , DNA/metabolismo , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Imunofenotipagem , Interferon-alfa/imunologia , Interferon gama/farmacologia , Interleucina-17/imunologia , Interleucinas/imunologia , Enteropatias/diagnóstico , Enteropatias/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Fenótipo , Fosforilação/efeitos dos fármacos , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/imunologia , Fator de Transcrição STAT1/metabolismo , Síndrome , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Ativação Transcricional
18.
Clin Immunol ; 146(3): 248-61, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23416241

RESUMO

Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8(+) T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.


Assuntos
Síndromes de Imunodeficiência/genética , Subunidade alfa de Receptor de Interleucina-2/deficiência , Autoimunidade/imunologia , Linhagem Celular , Proliferação de Células , Criança , Citocinas/sangue , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Mutação , Pele/imunologia , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia
19.
Antioxid Redox Signal ; 18(12): 1491-6, 2013 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-23216310

RESUMO

NADPH oxidase is known to modulate the arterial tone, but the role of its specific subunits is still unclear. The objective of this study was to compare the role of p47 and gp91phox (NOX2) on artery dilatation. We conducted a multicenter study enrolling 30 patients with chronic granulomatous disease (CGD) (25 with NOX2 deficiency and 5 with p47(phox) deficiency) and 30 healthy subjects (HS), matched for gender and age, in whom flow-mediated dilation (FMD), serum activity of NOX2 (soluble NOX2-derived peptide [sNOX2-dp]), urinary isoprostanes (8-iso-PGF2α), and platelet production of isoprostanes and NOX2 were determined. Compared to HS, patients with CGD had significantly higher FMD and lower sNOX2-dp and 8-iso-PGF2α levels. Compared to patients with NOX2 deficiency and HS, patients with p47(phox) hereditary deficiency had intermediate FMD and oxidative stress, that is, higher and lower FMD and lower and higher isoprostanes compared to HS and patients with NOX2 deficiency, respectively. In agreement with this finding, an ex vivo study showed higher inhibition of NOX2 activity and lower isoprostane formation in platelets from patients with NOX2 deficiency compared to platelets from ones with p47(phox) deficiency. Our observations lead to the hypothesis that oxidants are implicated in artery vasoconstriction.


Assuntos
Doença Granulomatosa Crônica/fisiopatologia , Glicoproteínas de Membrana/deficiência , NADPH Oxidases/deficiência , Vasodilatação , Adolescente , Plaquetas/enzimologia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Criança , Feminino , Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/urina , Humanos , Isoprostanos/urina , Masculino , NADPH Oxidase 2 , Adulto Jovem
20.
Am J Med Genet A ; 158A(4): 917-21, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22419483

RESUMO

Bohring-Opitz syndrome (BOS) is a rare condition characterized by facial anomalies, multiple malformations, failure to thrive and severe intellectual disabilities. Recently, the cause was identified on the basis of de novo heterozygous mutations in the ASXL1 gene. We report on two novel cases carrying two previously undescribed mutations (c.2407_2411del5 [p.Q803TfsX17] and c.2893C>T [p.R965X]). These new data further support ASXL1 as cause of BOS and may contribute to a more precise definition of the phenotype caused by the disruption of this gene.


Assuntos
Anormalidades Múltiplas/genética , Craniossinostoses/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Criança , Códon sem Sentido/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Lactente , Masculino , Fenótipo
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