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Clin Immunol ; 205: 1-5, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31071452


Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

J Clin Immunol ; 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29995221


PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rß1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rß1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rß1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rß1-deficient patients with a complete loss of IL-12Rß1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rß1 deficiency.

J Allergy Clin Immunol ; 138(1): 241-248.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936803


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.

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
J Pediatr ; 163(1 Suppl): S12-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23773588


OBJECTIVE: Haemophilus influenzae type b (Hib) conjugate vaccine was included into the national vaccination schedule of Ukraine in 2006. The objective of this study was to demonstrate the effectiveness of Hib conjugate vaccine against radiologically-confirmed hospitalized pneumonia in children. STUDY DESIGN: Children <2 years old with radiologically confirmed pneumonia admitted to 11 participating hospitals in Kiev and Dnepropetrovsk between April 2007 and June 2009 were included in a case-control evaluation. Four controls were matched to each case by date of birth (within 14 days) and outpatient clinic. We estimated ORs for vaccination and vaccine effectiveness ((1 - OR)*100%) using conditional logistic regression, adjusting for comorbid conditions and contraindications for vaccination. RESULTS: We enrolled 188 case-children and 735 controls. Median age was 16 months (range 4-24 months). Fifty-one percent of cases and 67% of controls received ≥1 doses of Hib conjugate vaccine; 26% of cases and 37% of controls received ≥3 doses. The effectiveness of ≥1 dose Hib conjugate vaccine was estimated at 45% (95% CI 18%-63%). CONCLUSIONS: Our study showed that Hib infections are important causes of hospitalized radiologically confirmed pneumonia in young children in Ukraine.

Criança Hospitalizada/estatística & dados numéricos , Infecções por Haemophilus/epidemiologia , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/administração & dosagem , Haemophilus influenzae tipo b/imunologia , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/prevenção & controle , Cápsulas Bacterianas/imunologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Infecções por Haemophilus/diagnóstico por imagem , Vacinas Anti-Haemophilus/imunologia , Humanos , Programas de Imunização , Lactente , Masculino , Pneumonia Bacteriana/diagnóstico por imagem , Radiografia , Ucrânia/epidemiologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia
J Med Genet ; 50(9): 567-78, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23709754


BACKGROUND: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. OBJECTIVE: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. RESULTS: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. CONCLUSIONS: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

Candidíase Mucocutânea Crônica/genética , Mutação , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/metabolismo , Europa Oriental , Predisposição Genética para Doença , Humanos , Testes Imunológicos , Leucócitos Mononucleares/imunologia , Pessoa de Meia-Idade , Fosforilação , Estrutura Terciária de Proteína
J Exp Med ; 208(8): 1635-48, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21727188


Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/ß, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/ß, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Modelos Moleculares , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Mutação em Linhagem Germinativa/genética , Humanos , Immunoblotting , Interferon gama/sangue , Interferon gama/metabolismo , Interleucinas/metabolismo , Masculino , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor de Interferon alfa e beta/imunologia , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA