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1.
Int Arch Allergy Immunol ; 181(7): 540-550, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32512560

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease. METHODS: Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochrome b558 were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results. RESULTS: The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carried CYBB variants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carried NCF1 variants, 4 (17.4%) carried CYBA variants, and 3 (13%) carried NCF2 variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG in CYBB (OMIM#300481) and a novel c.251_263del13bp in CYBA (OMIM#608508) were also investigated. CONCLUSIONS: Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case with CYBB variant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/complicações , Humanos , Lactente , Infecções/etiologia , Masculino , NADPH Oxidase 2/genética , NADPH Oxidases/deficiência , NADPH Oxidases/genética , Estudos Retrospectivos
2.
Medicine (Baltimore) ; 99(23): e20599, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502033

RESUMO

Pediatricians are unfamiliar with chronic granulomatous disease (CGD) because of its rarity and paucity of available data, potentially leading to misdiagnosis, late treatments, and mortality. The main purpose of this study was to summarize the clinical manifestations and auxiliary examination findings of four children with CGD confirmed by genetic testing.This was a case series study of children hospitalized at the Pediatric Respiratory Department of Shandong Provincial Hospital. The clinical, laboratory, treatment, and prognosis data were analyzed.All 4 children were boys. Two were brothers. The children's age was from 34 days to 3 years and 2 months at disease onset. The manifestations were repeated pulmonary infection, lymphadenitis, skin infection, and granuloma formation. Pulmonary infections were common. Abnormal responses were common after BCG vaccination. Thoracic computed tomography (CT) mainly showed nodules and masses, while the consolidation area in CT images reduced slowly. No abnormalities in cellular immune functions and immunoglobulin were found. The disease in all four children was confirmed by genetic testing. Long-term antibiotics and anti-fungal drugs were needed to prevent bacterial and fungal infections.CGD should be considered in children with repeated severe bacterial and fungal infections. Abnormal responses after BCG vaccination and nodular or mass-shaped consolidation in thoracic CT images should hint toward CGD. Gene sequencing could provide molecular evidence for diagnosis. The treatments of CGD include the prevention and treatment of infections and complications. Immunologic reconstitution treatment is currently the only curative treatment for CGD.


Assuntos
Testes Genéticos/métodos , Doença Granulomatosa Crônica/fisiopatologia , Pré-Escolar , Progressão da Doença , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Masculino , Tórax/diagnóstico por imagem , Tórax/patologia , Tomografia Computadorizada por Raios X
3.
J Neuroimmunol ; 343: 577229, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247876

RESUMO

Chronic granulomatous disease (CGD) is an uncommon genetic immunodeficiency disorder affecting neutrophil function, characterized by recurrent bacterial and fungal infections. X-linked carriers of CGD have an increased risk of autoimmune disorders, in particular lupus like disorders. We describe the case of a 37 years old female carrier of X-linked CGD, who presented with clinical features and serology consistent with a definite diagnosis of Systemic lupus erythematosus (SLE), with rare immune mediated neurological manifestations including secondary central nervous system (CNS) vasculitis and Longitudinally extensive transverse myelitis (LETM), responsive to immunomodulation. These neurological manifestations have not been described previously in carriers of CGD. We recommend early diagnosis of these immune mechanisms, especially in X-linked carriers of CGD, and appropriate immunomodulation in order to improve life expectancy and improve neurological outcome.


Assuntos
Doença Granulomatosa Crônica/complicações , Lúpus Eritematoso Sistêmico/complicações , Adulto , Anti-Inflamatórios/uso terapêutico , Feminino , Doença Granulomatosa Crônica/tratamento farmacológico , Doença Granulomatosa Crônica/genética , Heterozigoto , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metilprednisolona/uso terapêutico , Mielite Transversa/etiologia , Vasculite do Sistema Nervoso Central/etiologia
4.
PLoS One ; 15(4): e0230665, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251485

RESUMO

Phagocytes in patients with chronic granulomatous disease (CGD) do not generate reactive oxidative species (ROS), whereas nitric oxide (NO) production is increased in response to the calcium ionophore A23187 in CGD phagocytes compared with healthy phagocytes. Recently, patients with X-linked CGD (X-CGD) have been reported to show higher flow-mediated dilation, suggesting that endothelial cell function is affected by NO production from phagocytes. We studied NOS3 and EDN1 mRNA and protein expression in human umbilical vein endothelial cells (HUVECs) in a co-culture system with neutrophils from X-CGD patients. HUVECs were co-cultured for 30 minutes with human neutrophils from X-CGD or healthy participants in response to A23187 without cell-to-cell contact. The expression of NOS3 and EDN1 mRNA in HUVECs was quantified by real-time polymerase chain reaction. Moreover, we demonstrated the protein expression of eNOS, ET-1, and NFκB p65, including phosphorylation at Ser1177 of eNOS and Ser536 of NFκB p65. Neutrophils from X-CGD patients showed significantly higher NO and lower H2O2 production in response to A23187 than healthy neutrophils in vitro. Compared with healthy neutrophils, X-CGD neutrophils under A23187 stimulation exhibited significantly increased NO and decreased H2O2, and promoted downregulated NOS3 and EDN1 expression in HUVECs. The total expression and phosphorylation at Ser1177 of eNOS and ET-1 expression were significantly decreased in HUVECs co-cultures with stimulated X-CGD neutrophils. Also, phosphorylation at Ser536 of NFκB p65 were significantly decreased. In conclusions, eNOS and ET-1 significantly down-regulated in co-culture with stimulated X-CGD neutrophils through their excessive NO and the lack of ROS production. These findings suggest that ROS generated from neutrophils may mediate arterial tone affecting eNOS and ET-1 expression via their NO and ROS production.


Assuntos
Técnicas de Cocultura , Regulação para Baixo , Endotelina-1/metabolismo , Doença Granulomatosa Crônica/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Adolescente , Estudos de Casos e Controles , Endotelina-1/genética , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação , RNA Mensageiro/genética , Fator de Transcrição RelA/metabolismo
5.
Nat Med ; 26(2): 200-206, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31988463

RESUMO

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.


Assuntos
Cromossomos Humanos X , Terapia Genética/métodos , Doença Granulomatosa Crônica/genética , Lentivirus/genética , Adolescente , Antígenos CD34/genética , Criança , Pré-Escolar , Comorbidade , Inativação Gênica , Genes Reguladores , Vetores Genéticos , Doença Granulomatosa Crônica/terapia , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , NADPH Oxidases/genética , Neutrófilos/metabolismo , Segurança do Paciente , Regiões Promotoras Genéticas , Condicionamento Pré-Transplante , Resultado do Tratamento , Reino Unido , Estados Unidos , Adulto Jovem
7.
Acta Microbiol Immunol Hung ; 67(1): 56-60, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31847541

RESUMO

Chronic granulomatous disease is a non-prevalent genetic disorder due to different structural gene mutations encoding components of nicotinamide adenine dinucleotide phosphate oxidase complex. Nicotinamide adenine dinucleotide phosphate oxidase is a complex made by a group of five proteins (subunit) and plays an important role in the innate immune system. Five structural genes are responsible for encoding each subunit, in which cytochrome b-245 alpha chain (also known as p22-phox) is encoded by CYBA gene. CYBA gene mutation leads to a group of autosomal dominant chronic granulomatous disease. Decreased level or lack of nicotinamide adenine dinucleotide phosphate oxidase leaves affected individuals vulnerable to many types of infections and excessive inflammation. In this study, a family affected by BCGitis caused by a novel intronic autosomal recessive CYBA mutation (88,713,158 C > T) has been described. The proband is a 5-year-old girl with chronic granulomatous disease who was referred to the clinic due to BCGitis. The culprit mutation was detected following whole genome sequencing and was confirmed among the family members by Sanger sequencing. Being symptom-free at the time of diagnosis, despite the proband's mother homozygosity, was a characteristic feature of this report. Remarkably, none of the CYBA-mutated members, as a known chronic granulomatous disease causing gene, has expressed symptoms other than regional lymph node enlargements. This might explain the gene mutation site importance in demonstrating different manifestations.


Assuntos
Família , Genes Recessivos , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , NADPH Oxidases/genética , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Linfonodos/patologia , Masculino , Mutação , Sequenciamento Completo do Genoma
8.
Front Immunol ; 10: 2236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681257

RESUMO

Background: Chronic granulomatous disease (CGD) is caused by a malfunctioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to impaired bacterial and fungal killing and hyperinflammation. Objective: To characterize macrophage subsets and cytokine/chemokine signaling loops involved in CGD tissue hyperinflammation. Methods: Cytokine/chemokine production and surface marker expression were analyzed in inflamed tissue of four CGD patients and compared to cytokine/chemokine released by CGD macrophages upon priming to different macrophage subpopulations. Furthermore, the re-priming capacity of CGD pro-inflammatory M1 to M2a anti-inflammatory macrophages was evaluated. Results: In human CGD inflammatory tissue, IL-18 and IFN-γ were detected in significant quantity. Immunofluorescence analysis identified macrophages as one source of IL-18 in inflamed tissue. In vitro, CGD macrophages could be primed and re-primed into all inflammatory/anti-inflammatory macrophage subpopulations. IL-18 was also released by M1 CGD and control macrophages. Conclusion: CGD pro-inflammatory M1 macrophages remain M1 primed in vivo. As CGD M1 macrophages can be re-primed to anti-inflammatory M2a phenotype in vitro, macrophages are kept in M1 state in vivo by a persistent pro-inflammatory environment. Our results suggest a paracrine signaling loop between M1 macrophage derived IL-18 and non-macrophage derived IFN-γ maintaining macrophage pro-inflammatory activity in CGD tissue.


Assuntos
Doença Granulomatosa Crônica/imunologia , Interferon gama/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Comunicação Parácrina/imunologia , Transdução de Sinais/imunologia , Adolescente , Adulto , Criança , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/patologia , Humanos , Lactente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interferon gama/genética , Interleucina-18/genética , Macrófagos/patologia , Masculino , Comunicação Parácrina/genética , Transdução de Sinais/genética
9.
Emerg Infect Dis ; 25(12): 2319-2321, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31742513

RESUMO

We report a case of Aspergillus felis infection in a patient with chronic granulomatous disease who had overlapping features of invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Identifying the species responsible for aspergillosis by molecular methods can be crucial for directing patient management and selection of appropriate antifungal agents.


Assuntos
Aspergilose/diagnóstico , Aspergilose/etiologia , Aspergillus , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/diagnóstico , Adulto , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus/efeitos dos fármacos , Aspergillus/genética , Biomarcadores , Doença Granulomatosa Crônica/genética , Humanos , Aspergilose Pulmonar Invasiva/diagnóstico , Contagem de Leucócitos , Masculino , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
Transplant Proc ; 51(9): 3155-3158, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611125

RESUMO

We present a case report of a boy diagnosed with both chronic granulomatous disease (CGD) and familial celiac disease (CD) who underwent cord blood transplantation from a partially matched sibling donor. The presentation of CD resembled Crohn-like enteropathy, which is a canonical manifestation of CGD. Nearly 1 year post-hematopoietic stem cell transplantation (HSCT), a gluten-containing diet was reintroduced, and no reappearance of clinical, serologic, or histologic markers of CD was observed. The relatively high incidence of rare genetic diseases in pediatric patients suggests the need for additional caution in the interpretation of symptoms mimicking already known hallmarks of more common conditions. In addition, the presented data confirm the previous rare observations that allogeneic HSCT leads to durable induction of gluten tolerance in patients with CD, which can warrant its use in patients with refractory subtypes of CD.


Assuntos
Doença Celíaca/complicações , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/cirurgia , Doença Celíaca/genética , Criança , Pré-Escolar , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Masculino , Irmãos , Transplante Homólogo
11.
BMJ Case Rep ; 12(8)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473638

RESUMO

X-linked carriers of chronic granulomatous disease (CGD) may become phenotypically affected if substantial skewing from lyonisation occurs. We describe a 73-year-old female carrier with an overt CGD phenotype due to skewed lyonisation, complicated by macrophage activation syndrome (MAS)/haemophagocytic lymphohistiocytosis (HLH) secondary to Burkholderiacepacia complex septicaemia that was successfully treated with a combination of three antibiotics, an antifungal, granulocyte colony stimulating factor, intravenous immune globulin (IVIG) and ciclosporin. Fully phenotypic immunodeficiency is possible in X-linked CGD carriers when skewed lyonisation occurs, rendering such patients to all the same sequelae of CGD such as MAS/HLH. MAS/HLH should be thoroughly excluded when evaluating 'cepacia syndrome' in non-CGD patients.


Assuntos
Infecções por Burkholderia/complicações , Complexo Burkholderia cepacia , Doença Granulomatosa Crônica/microbiologia , Linfo-Histiocitose Hemofagocítica/microbiologia , Síndrome de Ativação Macrofágica/microbiologia , Sepse/microbiologia , Doença Aguda , Idoso , Infecções por Burkholderia/genética , Infecções por Burkholderia/microbiologia , Feminino , Doença Granulomatosa Crônica/genética , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Síndrome de Ativação Macrofágica/genética , Sepse/genética , Síndrome , Inativação do Cromossomo X
13.
Iran J Allergy Asthma Immunol ; 18(4): 447-451, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31522453

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Heterozigoto , Fenótipo , Inativação do Cromossomo X , Adolescente , Biomarcadores , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Avaliação de Sintomas
14.
Autoimmunity ; 52(7-8): 256-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556326

RESUMO

Blau syndrome is an autosomal dominant rare disease caused by mutations in NOD2 gene. Less than 200 patients published with Blau Syndrome Worldwide. We reported a 41-year old female Turkish patient diagnosed as Blau syndrome. Granulomatous dermatitis and severe headache, as well as recurrent chest and pelvic pain have been present since she was 8 years old. Arthritis started when she was teenage, hypertension diagnosed when she was 20 and other symptoms also occurred during the lifetime (severe preeclampsia, ischemic stroke, recurrent hemiparesis, recurrent-transient-vision-loss and renal-artery-stenosis). Genomic DNA was isolated from peripheral blood and 12 genes sequenced in Autoinflammatory panel on IonTorrent-S5-NGS platform with Parseq-VariFind™AIPassay. NGS analysis showed 107 variants in in the index case, mainly benign with no strong association with Blau syndrome. Additionally, we identified one very rare missense mutation in NOD2 gene (c2803G>A, p.Val935Met) and in silico assessment of the mutation indicated possible pathogenic significance and strong association with Blau syndrome. In addition, we analyzed family members of the index case and identified the same mutation in NOD2 gene. The segregation analysis shows the presence of the same mutant allele in NOD2 gene in the index case affected sister, as well as in her son with arthralgia, while in her non affecter brother we didn't detect the Val935Met mutation in NOD2 gene. Blau Syndrome is known as a very rare disease, mainly caused by mutations in NOD2 gene. Missense mutation diagnosed in our case could be responsible for the phenotype of the index case. Our results indicate the importance of NGS testing and its major role in the detection of rare mutations that may responsible for the onset of autoinflammatory disorders.


Assuntos
Artrite/genética , Dermatite/genética , Doença Granulomatosa Crônica/genética , Cefaleia/genética , Mutação de Sentido Incorreto , Proteína Adaptadora de Sinalização NOD2/genética , Acidente Vascular Cerebral/genética , Sinovite/genética , Uveíte/genética , Adulto , Alelos , Artrite/diagnóstico , Artrite/fisiopatologia , Criança , Dermatite/diagnóstico , Dermatite/fisiopatologia , Éxons , Feminino , Expressão Gênica , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/fisiopatologia , Cefaleia/diagnóstico , Cefaleia/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoidose , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Sinovite/diagnóstico , Sinovite/fisiopatologia , Uveíte/diagnóstico , Uveíte/fisiopatologia
15.
Stem Cell Reports ; 13(4): 590-598, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31543470

RESUMO

Mutations in the NADPH oxidase, which is crucial for the respiratory burst in phagocytes, result in chronic granulomatous disease (CGD). The only curative treatment option for CGD patients, who suffer from severe infections, is allogeneic bone marrow transplantation. Over 90% of patients with mutations in the p47phox subunit of the oxidase complex carry the deletion c.75_76delGT (ΔGT). This frequent mutation most likely originates via gene conversion from one of the two pseudogenes NCF1B or NCF1C, which are highly homologous to NCF1 (encodes p47phox) but carry the ΔGT mutation. We applied CRISPR/Cas9 to generate patient-like p47-ΔGT iPSCs for disease modeling. To avoid unpredictable chromosomal rearrangements by CRISPR/Cas9-mediated cleavage in the pseudogenes, we developed a gene-correction approach to specifically target NCF1 but leave the pseudogenes intact. Functional assays revealed restored NADPH oxidase activity and killing of bacteria in corrected phagocytes as well as the specificity of this approach.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Doença Granulomatosa Crônica/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , NADPH Oxidases/genética , Ativação Enzimática , Expressão Gênica , Marcação de Genes , Loci Gênicos , Granulócitos/imunologia , Granulócitos/metabolismo , Doença Granulomatosa Crônica/metabolismo , Humanos , Íntrons , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , NADPH Oxidases/metabolismo , Fagocitose/imunologia , Pseudogenes/genética , Homologia de Sequência
16.
J Clin Immunol ; 39(8): 762-775, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31456102

RESUMO

PURPOSE: Chronic granulomatous disease (CGD) is the most common phagocyte defect disease. Here, we describe 114 CGD patients in our center and report a rare female infant with XL-CGD to provide a better understanding of diagnosis, treatment, and prenatal diagnosis of CGD. METHOD: Patients were diagnosed by DHR-1,2,3 flow cytometry assays and gene analysis. X chromosome inactivation analysis and gp91phox protein test were used for a female infant with XL-CGD. RESULTS: XL-CGD accounts for the majority of cases in China and results in higher susceptibility to some infections than AR-CGD. The DHR assay can help diagnose CGD quickly, and atypical results should be combined with clinical manifestations, genetic analysis, and regular follow-up. For prenatal diagnosis, both gDNA and cDNA genotypes of amniotic fluid cells should be identified, and cord blood DHR assays should be performed to identify female XL-CGD patients.


Assuntos
Testes Genéticos/estatística & dados numéricos , Doença Granulomatosa Crônica/diagnóstico , Diagnóstico Pré-Natal/estatística & dados numéricos , Inativação do Cromossomo X/genética , Líquido Amniótico/citologia , Criança , Pré-Escolar , China/epidemiologia , Feminino , Citometria de Fluxo/estatística & dados numéricos , Seguimentos , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Masculino , NADPH Oxidase 2/genética , Rodaminas/química
17.
Mol Genet Genomic Med ; 7(9): e854, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31364312

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immune deficiency caused by mutations in the genes encoding the structural components of the phagocyte NADPH oxidase. As a result, the patients cannot generate sufficient amounts of reactive oxygen species required for killing pathogenic microorganisms. METHODS: We analyzed NADPH oxidase activity and component expression in neutrophils, performed genomic DNA and cDNA analysis, and used mRNA splicing prediction tools to evaluate the impact of mutations. RESULTS: In two patients with CGD, we had previously found mutations that cause aberrant pre-mRNA splicing. In one patient an exonic mutation in a cryptic donor splice site caused the deletion of the 3' part of exon 6 from the mRNA of CYBB. This patient suffers from X-linked CGD. The second patient, with autosomal CGD, has a mutation in the donor splice site of intron 1 of CYBA that activates a cryptic donor splice site downstream in intron 1, causing the insertion of intronic sequences in the mRNA. The third patient, recently analyzed, also with autosomal CGD, has a mutation in intron 4 of CYBA, 15 bp from the acceptor splice site. This mutation weakens a branch site and activates a cryptic acceptor splice site, causing the insertion of 14 intronic nucleotides into the mRNA. CONCLUSION: We found three different mutations, one exonic, one in a donor splice site and one intronic, that all caused missplicing of pre-mRNA. We analyzed these mutations with four different splice prediction programs and found that predictions of splice site strength, splice enhancer and splice silencer protein binding and branch site strength are all essential for correct prediction of pre-mRNA splicing.


Assuntos
Doença Granulomatosa Crônica/genética , Sítios de Splice de RNA , Processamento de RNA , Ativação Transcricional , Alelos , Éxons , Feminino , Doença Granulomatosa Crônica/metabolismo , Humanos , Íntrons , Masculino , Mutação , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo
18.
Allergol. immunopatol ; 47(4): 372-327, jul.-ago. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-186509

RESUMO

Introduction: Chronic granulomatous disease (CGD) is a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH oxidase complex activity. Although the effect of CGD mainly reflects the phagocytic compartment, B cell responses are also impaired in patients with CGD. Materials and methods: Flow cytometric analysis was performed on peripheral blood samples from 35 CGD patients age-matched with healthy controls (HC). The target cells of our study were the naive (IgD+/CD27-), memory (IgD-/CD27+), and B1a (CD5+) cells. Immunoglobulins (Igs) were also measured. This study was performed in a Latin American cohort. Results: We found significantly higher levels of naive B cells and B1a cells, but lower levels of memory B cells were found in CGD patients compared to HC. There was no significant difference of cell percentages per inheritance type. Discussion: Our findings suggest that the deficiency of NADPH oxidase components can affect the differentiation of naive B cells to memory B cells. Consequently, memory cells will be low, which also influenced the expression of CD27 in memory B cells and as a result, the percentage of naive cells increases. An altered phenotype of B lymphocytes in CGD patients may contribute to the opportunistic infections and autoimmune disorders that are seen in this disease


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Linfócitos B/imunologia , Subpopulações de Linfócitos B/imunologia , Doença Granulomatosa Crônica/imunologia , NADPH Oxidase 2/genética , Separação Celular , Estudos de Coortes , Citometria de Fluxo , Doença Granulomatosa Crônica/genética , Memória Imunológica , México , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
20.
Allergol Immunopathol (Madr) ; 47(4): 372-377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31176517

RESUMO

INTRODUCTION: Chronic granulomatous disease (CGD) is a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH oxidase complex activity. Although the effect of CGD mainly reflects the phagocytic compartment, B cell responses are also impaired in patients with CGD. MATERIALS AND METHODS: Flow cytometric analysis was performed on peripheral blood samples from 35 CGD patients age-matched with healthy controls (HC). The target cells of our study were the naive (IgD+/CD27-), memory (IgD-/CD27+), and B1a (CD5+) cells. Immunoglobulins (Igs) were also measured. This study was performed in a Latin American cohort. RESULTS: We found significantly higher levels of naive B cells and B1a cells, but lower levels of memory B cells were found in CGD patients compared to HC. There was no significant difference of cell percentages per inheritance type. DISCUSSION: Our findings suggest that the deficiency of NADPH oxidase components can affect the differentiation of naive B cells to memory B cells. Consequently, memory cells will be low, which also influenced the expression of CD27 in memory B cells and as a result, the percentage of naive cells increases. An altered phenotype of B lymphocytes in CGD patients may contribute to the opportunistic infections and autoimmune disorders that are seen in this disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Doença Granulomatosa Crônica/imunologia , NADPH Oxidase 2/genética , Adolescente , Adulto , Separação Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Doença Granulomatosa Crônica/genética , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Masculino , México , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
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