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2.
Med Microbiol Immunol ; 205(5): 425-34, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27240652

RESUMO

Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS), which primarily affects human immunodeficiency virus (HIV)-infected adults with advanced immunodeficiency. Currently, only limited prevalence data for HHV-8 infection in HIV-infected children living in non-endemic areas are available. This multicenter cross-sectional study was conducted in four university hospitals in Germany specializing in pediatric HIV care. Stored serum specimens obtained from 207 vertically HIV-1-infected children and adolescents were tested for antibodies against lytic and latent HHV-8 antigens. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall HHV-8 seroprevalence was 24.6 % (n = 51/207) without significant differences related to sex, age, or ethnicity. In univariate analysis, HHV-8 seropositivity was significantly associated with a child having being born outside Germany, maternal origin from sub-Saharan Africa, a history of breastfeeding, CDC immunologic category 3, and deferred initiation of antiretroviral therapy (>24 months of age). In multivariate analysis, a child's birth outside Germany was the only significant risk factor for HHV-8 seropositivity (odds ratio 3.98; 95 % confidence interval 1.27-12.42). HHV-8-associated malignancies were uncommon; only one patient had a history of KS. Serum specimen of vertically HIV-infected children and adolescents living in Germany showed a high HHV-8 seroprevalence. These findings suggest that primary HHV-8 infection-a risk factor for KS and other HHV-8-associated malignancies-occurs early in life. Thus, management of perinatally HIV-infected children should include testing for HHV-8 coinfection and should consider future risks of HHV-8-associated malignancies.


Assuntos
Anticorpos Antivirais/sangue , Infecções por HIV/complicações , Infecções por Herpesviridae/epidemiologia , Herpesvirus Humano 8/imunologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Emigrantes e Imigrantes , Grupos Étnicos , Feminino , Infecções por Herpesviridae/virologia , Humanos , Lactente , Masculino , Fatores de Risco , Estudos Soroepidemiológicos
4.
Curr Gene Ther ; 15(4): 416-27, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25981636

RESUMO

We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.


Assuntos
Terapia Genética/métodos , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Aspergilose/terapia , Aspergillus nidulans/patogenicidade , Criança , Deleção Cromossômica , Cromossomos Humanos Par 7 , Proteínas de Ligação a DNA/genética , Gammaretrovirus/genética , Terapia Genética/efeitos adversos , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Glicoproteínas de Membrana/genética , Síndromes Mielodisplásicas/etiologia , NADPH Oxidase 2 , NADPH Oxidases/genética , Proto-Oncogenes/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética
5.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25627830

RESUMO

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.


Assuntos
Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Incidência , Lactente , /epidemiologia , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Síndrome de Job/terapia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Neoplasias/etiologia , Fenótipo , Adulto Jovem
6.
Haematologica ; 99(8): 1395-402, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997149

RESUMO

Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment.


Assuntos
Neutropenia/diagnóstico , Neutropenia/terapia , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , Sistema de Registros , Adulto , Estudos de Coortes , Gerenciamento Clínico , Europa (Continente)/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Neutropenia/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Resultado do Tratamento , Adulto Jovem
7.
AIDS ; 28(4): 543-7, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24056069

RESUMO

BACKGROUND: HIV-1 seroreversion in infants with vertically transmitted HIV-1 infection who started ART in the first months of life has been reported in only a subset of patients. However, the reason why most infants remain seropositive despite similar treatment response is not understood. Here, we assessed whether HIV-1 seroreversion in maternally infected infants is associated with genetic determinants. METHODS: HIV-1-infected infants with a history of documented HIV-1 seroreversion were identified throughout Germany using a standardized questionnaire. At study entry immune reconstitution and anti-HIV-1 antibody expression were monitored as clinical parameters. To search for genetic determinants high-resolution HLA genotyping was performed. In addition, the coding sequence of the chemokine receptor CCR5 was analyzed by Sanger sequencing regarding potential mutations. RESULTS: Patients showed normal numbers and frequencies of lymphocyte subpopulations. Five out of eight patients still had seronegative HIV-1 antibody status at study entry. HLA genotyping revealed the enrichment of HLA-DQB1*03 and DQB1*06 alleles within the patient cohort. Only one patient was found to carry a 32 bp-deletion within the CCR5 gene. CONCLUSION: Our results indicate that the phenotype of HIV-1 seroreversion in infants might correlate with the presence of HLA class II alleles DQB1*03 and DQB1*06. This finding supports the idea of genetic predisposition determining HIV-1 seroreversion in vertically infected infants effectively treated with ART.


Assuntos
Antirretrovirais/uso terapêutico , Predisposição Genética para Doença , Infecções por HIV/congênito , Infecções por HIV/genética , HIV-1/isolamento & purificação , Cadeias beta de HLA-DQ/genética , Receptores CCR5/genética , Criança , Pré-Escolar , Feminino , Alemanha , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Inquéritos e Questionários
8.
J Clin Immunol ; 33(6): 1088-99, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23708964

RESUMO

PURPOSE: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. METHODS: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. RESULTS: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. CONCLUSION: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.


Assuntos
Núcleo Celular/metabolismo , Displasia Ectodérmica/imunologia , Fibroblastos/imunologia , Quinase I-kappa B/metabolismo , Síndromes de Imunodeficiência/imunologia , Poliendocrinopatias Autoimunes/imunologia , Transporte Ativo do Núcleo Celular/genética , Pré-Escolar , Citocinas/imunologia , Células HeLa , Humanos , Quinase I-kappa B/genética , Lactente , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto/genética , Proteólise , Células Th17/imunologia , Transgenes/genética
10.
AIDS Res Hum Retroviruses ; 28(9): 1161-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22251065

RESUMO

In the late 1980s an HIV-1 epidemic emerged in Romania that was dominated by subtype F1. The main route of infection is believed to be parenteral transmission in children. We sequenced partial pol coding regions of 70 subtype F1 samples from children and adolescents from the PENTA-EPPICC network of which 67 were from Romania. Phylogenetic reconstruction using the sequences and other publically available global subtype F sequences showed that 79% of Romanian F1 sequences formed a statistically robust monophyletic cluster. The monophyletic cluster was epidemiologically linked to parenteral transmission in children. Coalescent-based analysis dated the origins of the parenteral epidemic to 1983 [1981-1987; 95% HPD]. The analysis also shows that the epidemic's effective population size has remained fairly constant since the early 1990s suggesting limited onward spread of the virus within the population. Furthermore, phylogeographic analysis suggests that the root location of the parenteral epidemic was Bucharest.


Assuntos
Soropositividade para HIV/epidemiologia , HIV-1/genética , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Filogenia , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Adolescente , Sequência de Aminoácidos , Criança , Farmacorresistência Viral , Feminino , Variação Genética , Humanos , Masculino , Cadeias de Markov , Dados de Sequência Molecular , Filogeografia , Prevalência , Romênia/epidemiologia
11.
Blood ; 117(1): 53-62, 2011 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-20926771

RESUMO

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.


Assuntos
Antígenos CD/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfo-Histiocitose Hemofagocítica/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/genética , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Taxa de Sobrevida , Adulto Jovem
13.
J Allergy Clin Immunol ; 124(6): 1311-1318.e7, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20004786

RESUMO

BACKGROUND: Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T-cell activation requires Ca2+ influx through Ca2+-release activated Ca2+ (CRAC) channels encoded by the gene ORAI1. OBJECTIVE: Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function. METHODS: DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, and stromal interaction molecule (STIM) 1 and 2, as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors. RESULTS: We identified mutations in ORAI1 in patients from 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs. CONCLUSION: Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo. Despite almost ubiquitous ORAI1 expression, the channel has a nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients.


Assuntos
Canais de Cálcio/deficiência , Displasia Ectodérmica/metabolismo , Síndromes de Imunodeficiência/metabolismo , Doenças Musculares/metabolismo , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Mutação da Fase de Leitura , Homozigoto , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1 , Proteína ORAI2 , Molécula 1 de Interação Estromal , Molécula 2 de Interação Estromal , Transfecção
14.
J Pediatr ; 154(6): 888-94, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19230900

RESUMO

OBJECTIVE: To characterize common variable immunodeficiency disorder (CVID) in childhood. STUDY DESIGN: We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. RESULTS: Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). CONCLUSIONS: CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Adolescente , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/complicações , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Lactente , /imunologia , Masculino , Recidiva , Inquéritos e Questionários
15.
Pediatr Diabetes ; 10(4): 289-93, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18828793

RESUMO

To demonstrate that the 2-yr clinical follow-up of our patient strongly suggests that long-term therapy with posaconazole (POS) is safe and beneficial in treatment and prevention of relapses of, otherwise fatal, central nervous system mucormycosis. Mucormycosis is a very rare opportunistic mycotic infection of diabetic children. We present the 30-month follow-up of a 12-yr-old girl affected by diabetic ketoacidotic coma, complicated by rhinocerebral mucormycosis and successfully treated with POS at the initial daily dose of 5 mg/kg t.i.d. with fatty food for 3 wk, followed by a daily dose of 10 mg/kg in four doses for 2 months and then 20 mg/kg/d in four doses for 16 months and in two doses for further 5 months. The previous amphotericin B, granulocyte colony-stimulating factor, hyperbaric oxygen and nasal and left maxillary sinus surgical debridement therapy was ineffective in stopping the progression of the infection to the brain. The patient improved within 10 d with reduced ocular swelling and pain, and 6 months after therapy stop, she is in good health and cultures are sterile. This article demonstrates that POS may be a useful drug in mucormycosis in children. We also strongly draw the attention to the main preventive procedure against invasive fungal infection that is the correct management of antidiabetic therapy that prevents the predisposing temporary neutrophils activity deficit, contributing to a better survival rate of diabetic children.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/complicações , Mucormicose/tratamento farmacológico , Triazóis/uso terapêutico , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/tratamento farmacológico , Feminino , Seguimentos , Humanos , Mucormicose/complicações , Doenças Nasais/complicações , Doenças Nasais/tratamento farmacológico , Doenças Orbitárias/complicações , Doenças Orbitárias/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Triazóis/efeitos adversos
16.
J Allergy Clin Immunol ; 121(2): 375-382.e9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18155283

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is the most common inherited disorder of neutrophil function, is caused by mutations in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and results in recurrent bacterial infections. OBJECTIVE: We sought to investigate the expression and function of innate immune receptors on neutrophils in patients with CGD. METHODS: We quantified mRNA and protein expression of Toll-like receptors (TLRs), complement receptors, and chemokine receptors on neutrophils from 15 patients with CGD compared with that seen in healthy control subjects (n = 15) and control patients with bacterial pneumonia (n = 15). Phagocytosis, chemotaxis, and TLR function of isolated neutrophils were analyzed. The effect of NADPH oxidase inhibition on receptor expression and function was analyzed in control neutrophils. RESULTS: Neutrophils from patients with CGD had lower expression levels of TLR5, TLR9, CD11b, CD18, CD35, and CXCR1 compared with those from healthy control subjects, whereas similar or increased receptor expressions were found in patients without CGD but with bacterial pneumonia. Reduced TLR5 expression resulted in impaired neutrophil activation by bacterial flagella, reduced CD11b/CD18 expression was associated with impaired phagocytosis of Staphylococcus aureus, and reduced CXCR1 expression was associated with decreased chemotaxis. TLR5 and CD18 expression levels correlated with disease severity in patients with CGD. TLR5 and TLR9 expression were greater in patients with residual NADPH oxidase activity. Inhibition of the NADPH oxidase in control neutrophils in vitro decreased TLR5 and TLR9 expression and impaired TLR5 function. CONCLUSION: These results provide the first evidence that innate immune receptors are dysregulated in patients with CGD.


Assuntos
Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/metabolismo , Imunidade Inata , Neutrófilos/metabolismo , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Quimiotaxia de Leucócito , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Ativação de Neutrófilo , Fagocitose , Pneumonia Bacteriana/metabolismo , RNA Mensageiro/metabolismo , Receptores de Complemento/metabolismo , Receptores Imunológicos/genética , Receptores de Interleucina-8A/metabolismo , Índice de Gravidade de Doença , Staphylococcus aureus , Receptores Toll-Like/metabolismo
17.
Pediatr Radiol ; 37(2): 221-4, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17186232

RESUMO

"Hair-on-end" skull changes are typically seen in individuals suffering from thalassaemia. They are induced by widening of the diploic space due to marrow expansion that is a consequence of ineffective and excessive erythropoiesis. We present a child with severe congenital neutropenia who exhibited the typical hair-on-end sign on plain skull radiographs and MRI. In this patient the skull changes were very likely induced by the expansion of white blood cell precursors induced by long-term daily injections of recombinant human granulocyte colony stimulating factor (G-CSF) to treat his confounding disease. This case report is the first description of hair-on-end changes associated with the use of G-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Neutropenia/congênito , Neutropenia/diagnóstico por imagem , Osteoporose/induzido quimicamente , Osteoporose/diagnóstico por imagem , Crânio/anormalidades , Crânio/efeitos dos fármacos , Criança , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Neutropenia/tratamento farmacológico , Radiografia , Crânio/diagnóstico por imagem
18.
AIDS ; 16(15): 2083-5, 2002 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-12370510

RESUMO

Twenty-three HIV/hepatitis C virus (HCV)-co-infected patients received dose-escalated IFN-alpha (5 MIU/day) induction therapy for 10 weeks, followed by 36 weeks of thrice-weekly IFN-alpha treatment (5 MIU), both in combinations with ribavirin. Sustained HCV clearance was observed in three patients. Nine patients discontinued the study aas a result of adverse reactions such as anaemia, pancreatitis and depression. In HIV/HCV-co-infected patients, the therapeutic benefit of high-dose IFN-alpha therefore seems to be limited by its poor tolerability.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Antivirais/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Interferon-alfa/administração & dosagem , Masculino , Projetos Piloto , Ribavirina/administração & dosagem , Resultado do Tratamento
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