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3.
J Allergy Clin Immunol ; 139(3): 913-922, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27713077

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. OBJECTIVE: In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. METHODS: We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. RESULTS: Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. CONCLUSIONS: The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Adolescente , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Região de Troca de Imunoglobulinas , Lactente , Leucócitos Mononucleares , Masculino , Recombinação Genética , Hipermutação Somática de Imunoglobulina
4.
J Allergy Clin Immunol ; 138(1): 241-248.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936803

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.


Assuntos
Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologia
5.
Pediatr Blood Cancer ; 62(12): 2101-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26185101

RESUMO

AIM: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database. RESULTS: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene. CONCLUSION: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients.


Assuntos
Doença Granulomatosa Crônica , Glicoproteínas de Membrana/genética , Mutação , NADPH Oxidases/genética , Sistema de Registros , Abscesso/epidemiologia , Abscesso/etiologia , Abscesso/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Diarreia/epidemiologia , Diarreia/etiologia , Diarreia/genética , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Hispano-Americanos , Humanos , Lactente , Recém-Nascido , Doenças Linfáticas/epidemiologia , Doenças Linfáticas/etiologia , Doenças Linfáticas/genética , Masculino , NADPH Oxidase 2 , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/genética , Otite/epidemiologia , Otite/etiologia , Otite/genética , Pneumonia/epidemiologia , Pneumonia/etiologia , Pneumonia/genética , Sepse/epidemiologia , Sepse/etiologia , Sepse/genética , Dermatopatias/epidemiologia , Dermatopatias/etiologia , Dermatopatias/genética , Infecções Urinárias/epidemiologia , Infecções Urinárias/etiologia , Infecções Urinárias/genética
6.
J Exp Med ; 212(5): 619-31, 2015 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-25918342

RESUMO

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/imunologia , Homozigoto , Receptores de Interleucina/deficiência , Dermatopatias Genéticas/imunologia , Adulto , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/patologia , Criança , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
7.
J Clin Immunol ; 34(2): 146-56, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24402618

RESUMO

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.


Assuntos
Síndrome de Imunodeficiência com Hiper-IgM/epidemiologia , Ligante de CD40/deficiência , Ligante de CD40/genética , Pré-Escolar , Comorbidade , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Hispano-Americanos , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Lactente , Recém-Nascido , Infecção/diagnóstico , Infecção/etiologia , Pulmão/patologia , Masculino , Sistema de Registros , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
J Clin Immunol ; 32(1): 89-97, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22076597

RESUMO

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. Mutations in the gene encoding TACI (TNFRSF13B) were previously found to be associated with CVID. Previous studies have identified a variety of sequence variants in TACI where A181E and C104R were the most common, with variable frequencies in different ethnic populations. So far, no mutations were identified in the recently reported "TACI highly conserved" (THC) cytoplasmic domain, important for the induction of class switch recombination. Our study evaluated immunological and clinical data on a cohort of 28 Argentinean pediatric CVID patients and allowed the identification of two novel mutations in TNFRSF13B, including one, S231R, affecting the highly conserved THC domain. In contrast, none of the patients presented with A181E and C104R mutations.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Mutação , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adolescente , Substituição de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sequência de Bases , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ordem dos Genes , Humanos , Masculino , Linhagem , RNA Mensageiro/metabolismo
10.
Science ; 332(6025): 65-8, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21350122

RESUMO

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.


Assuntos
Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Candida albicans , Criança , Pré-Escolar , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Receptores de Interleucina-17/genética , Transdução de Sinais/genética , Células Th17/imunologia
13.
Hum Mutat ; 21(4): 451, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12655572

RESUMO

The block in differentiation from pro-B to pre-B cells results in a selective defect in the humoral immune response characteristic of human X-linked agammaglobulinemia (XLA). Mutations of Bruton tyrosine kinase (BTK) gene have been identified as the cause of XLA. Mutation detection is the most reliable method for making a definitive diagnosis, except when clinical and laboratory findings are distinctive and coupled with history of X-linked inheritance. To provide a definitive diagnosis to 40 families incorporated in the Argentinian Primary Immunodeficiencies Registry we analysed the BTK gene by SSCP analysis as screening method for XLA, followed by direct sequencing. The molecular defect was localized in 45 patients from 34 unrelated families. From the 34 independent mutations identified, 16 were previously undescribed, 31 were unique mutations, 22 were exonic single nucleotide changes (16 missense and 6 nonsense) and four intronic mutations. Because five families had clinical, immunological and inheritance data sufficient for a definitive diagnosis, our study allowed 37 patients from 29 families previously categorized probable/ possible XLA, have now definitive diagnosis leading to appropriate genetic counseling.


Assuntos
Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Mutação , Proteínas Tirosina Quinases/genética , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/epidemiologia , Argentina/epidemiologia , Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Humanos , Masculino , Polimorfismo Conformacional de Fita Simples
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