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1.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578351

RESUMO

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αß T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rß2-deficient than IL-12Rß1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.


Assuntos
Imunidade Inata/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium/imunologia , Humanos , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-23/deficiência , Interleucina-23/genética , Linhagem
2.
Nat Immunol ; 19(9): 973-985, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127434

RESUMO

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

3.
J Clin Immunol ; 37(8): 790-800, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28956255

RESUMO

INTRODUCTION: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations. METHOD: Seven affected individuals from five families were assessed retrospectively in this study. RESULTS: Of the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy. CONCLUSION: LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.


Assuntos
Abatacepte/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças Autoimunes/genética , Imunodeficiência de Variável Comum/genética , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/genética , Mutação/genética , Adolescente , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Criança , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/tratamento farmacológico , Intervalo Livre de Doença , Evolução Fatal , Feminino , Homozigoto , Humanos , Lactente , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Sepse , Turquia
4.
Proc Natl Acad Sci U S A ; 113(51): E8277-E8285, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930337

RESUMO

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.


Assuntos
Infecções Bacterianas/imunologia , Candidíase/imunologia , Micoses/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Alelos , Candida , Membrana Celular , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Recessivos , Estudo de Associação Genômica Ampla , Células HEK293 , Homozigoto , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Interleucina-17/metabolismo , Masculino , Mutação , Fases de Leitura Aberta , Linhagem , Receptores de Interleucina-17/metabolismo , Pele/microbiologia , Linfócitos T/citologia
5.
Hum Mol Genet ; 25(18): 4041-4051, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466202

RESUMO

For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.


Assuntos
Face/anormalidades , Síndromes de Imunodeficiência/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Transcrição Genética , Animais , Códon sem Sentido/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Helicases/genética , Face/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Síndromes de Imunodeficiência/fisiopatologia , Masculino , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Nucleares/biossíntese , Transcriptoma/genética
6.
J Allergy Clin Immunol ; 137(3): 879-88.e2, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26476480

RESUMO

BACKGROUND: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. OBJECTIVE: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia. METHODS: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. RESULTS: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. CONCLUSIONS: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.


Assuntos
Citoesqueleto/metabolismo , Homozigoto , Proteínas dos Microfilamentos/genética , Mutação , Multimerização Proteica , Viroses/etiologia , Viroses/metabolismo , Actinas/química , Actinas/metabolismo , Adolescente , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Degranulação Celular/genética , Degranulação Celular/imunologia , Sobrevivência Celular/genética , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Contagem de Linfócitos , Linfopenia , Masculino , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/metabolismo , Linhagem , Fenótipo , Multimerização Proteica/genética , Transporte Proteico , Irmãos , Transdução de Sinais , Dermatopatias/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Viroses/diagnóstico , Verrugas/patologia
7.
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
8.
J Allergy Clin Immunol ; 136(2): 402-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25724123

RESUMO

BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. RESULTS: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.


Assuntos
Infecções Bacterianas/complicações , Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndrome de Job/complicações , Fenótipo , Dermatopatias/complicações , Viroses/complicações , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Antígenos Virais/sangue , Antígenos Virais/imunologia , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/genética , Imunoglobulina M/sangue , Imunoglobulina M/genética , Lactente , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/mortalidade , Máquina de Vetores de Suporte , Análise de Sobrevida , Viroses/genética , Viroses/imunologia , Viroses/mortalidade
10.
Immunol Rev ; 264(1): 103-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25703555

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.


Assuntos
Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/etiologia , Mycobacterium tuberculosis/imunologia , Tuberculose/etiologia , Fatores Etários , Criança , Genes Dominantes , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
11.
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 , Infecção/diagnóstico , Infecção/epidemiologia , Infecção/etiologia , 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
12.
Clin Infect Dis ; 58(2): 204-13, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24186907

RESUMO

BACKGROUND: Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency. RESULTS: Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS: Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.


Assuntos
Candidíase/imunologia , Candidíase/patologia , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Recidiva
13.
Eur J Hum Genet ; 21(11): 1219-25, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23486536

RESUMO

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Face/anormalidades , Heterogeneidade Genética , Predisposição Genética para Doença , Síndromes de Imunodeficiência/genética , Mutação/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Criança , Demografia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/terapia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
J Pediatr Hematol Oncol ; 35(2): e81-3, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23018568

RESUMO

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndromic type of severe congenital neutropenia, associated with multiple organ abnormalities including facial, cardiac, and urogenital abnormalities, and increased visibility of superficial veins. The molecular pathophysiology of G6PC3 deficiency is associated with the disturbed glucose homeostasis, increased endoplasmic reticulum stress, and apoptosis in neutrophils. We report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation (p.Leu154Pro). Most remarkable is that the chronic neutropenia that originated from this novel G6PC3 genetic defect is also accompanied by some other unusual manifestations in this patient: myelokathexis and hypercholesterolemia.


Assuntos
Glucose-6-Fosfatase/genética , Mutação , Neutropenia/congênito , Adolescente , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/tratamento farmacológico , Neutropenia/genética
15.
Pediatr Transplant ; 16(5): 451-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22594916

RESUMO

SCID is characterized by profound deficiencies of T and B lymphocytes. HSCT is the only curative treatment for children with SCID. The clinical characteristics and outcome of 30 HLA-haploidentical transplantations in 18 patients (15 SCID, two Omenn syndrome, and one MHC Class II deficiency) are reported here. The age of patients at diagnosis ranged from one and half to nine months (median: four months). The median time was one month between the diagnosis and the time of the initial transplantation. Infused CD34+ stem cell dose was ranged between 7 and 94.2 × 10(6) /kg. Nine of 18 patients were found to be positive for CMV antigenemia at diagnosis; therefore, none of them received a conditioning regimen. The most common complication was graft failure (61%), so repeated transplantations (two to four) were performed in seven patients. The mean time of lymphoid engraftment was 17.5 days (median: 16, range: 11-29 days). Ten of 15 SCID (67%) patients survived with a stable complete donor chimerism. However, all three non-SCID patients died. In conclusion, in the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a readily available treatment option especially for patients with SCID, offering a high chance of cure.


Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Imunodeficiência Combinada Severa/cirurgia , Seleção do Doador , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Humanos , Lactente , Masculino , Pais , Complicações Pós-Operatórias/epidemiologia , Reoperação/estatística & dados numéricos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Taxa de Sobrevida , Resultado do Tratamento
16.
J Clin Immunol ; 32(5): 961-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22547079

RESUMO

Selective IgA deficiency (IgAD) is considered as the most common primary immunodeficiency. Although the vast majority of affected individuals are asymptomatic, symptomatic patients suffer from recurrent infections, allergies and autoimmune diseases. In the present study, we aimed to investigate the clinical and laboratory features of children with IgAD in a tertiary children's hospital in Turkey. The medical records of 118 patients (63 males, 55 females) aged 4-18 years (median: 7 years) seen from 2006 to 2011 were retrospectively reviewed. The most common clinical condition was infectious disease (99 patients, 83.9 %), followed by allergic (51 patients, 43.2 %) and autoimmune (20 patients, 17 %) disorders. Serum IgG, IgM and IgE levels were increased in 61 %, 22 % and 37.3 % of patients, respectively. Serum IgG subclasses were measured in 65 patients, and only 4 (6.2 %) patients had IgG2 subclass deficiency. Autoantibodies (ANA, anti-dsDNA, antigliadin IgA and IgG, tissue transglutaminase IgA and IgG, anti-TPO and anti-TG) were evaluated in 84 patients. Autoantibodies were detected in 26 (31 %) patients, only 10 had an autoimmune disorder. Sixty-one patients were followed for more than 6 months (mean: 2 years, range: 0.5-5 years), and none of them resolved during this period. Being the most comprehensive study conducted in Turkey, we believe it has importance in providing significant data on the clinical and laboratory characteristics of children with IgAD.


Assuntos
Deficiência de IgA/complicações , Adolescente , Autoanticorpos/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Deficiência de IgA/diagnóstico , Deficiência de IgA/imunologia , Imunoglobulinas/sangue , Infecção/etiologia , Infecção/imunologia , Masculino , Estudos Retrospectivos , Turquia
17.
PLoS One ; 6(4): e18524, 2011 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-21533230

RESUMO

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rß1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rß1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rß1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rß1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rß1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.


Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/genética , Tuberculose/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Marrocos , Linhagem , Índice de Gravidade de Doença , Turquia
18.
Am J Hum Genet ; 88(6): 796-804, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21596365

RESUMO

Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.


Assuntos
Centrômero/genética , Metilação de DNA/genética , Proteínas Repressoras/genética , Dedos de Zinco , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Epigenômica , Face/anormalidades , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Mutação , Linhagem
19.
Turk J Pediatr ; 52(4): 348-53, 2010 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21043378

RESUMO

Recurrent bacterial meningitis is an uncommon but life-threatening condition. The aim of this study was to evaluate the demographic, clinical, microbiological, and radiological features of recurrent bacterial meningitis in children. Fourteen patients (10 male, 4 female) treated for recurrent bacterial meningitis were reviewed. The mean age of the patients was 87 months (range: 6 months to 13 years). There were 67 episodes of meningitis documented in these 14 patients. Six patients had developmental anatomical defects, five had traumatic anatomical defects and three had primary immune deficiency diseases as predisposing conditions. We suggest that, in a case of recurrent meningitis, a pediatrician should question and examine the patient carefully in search of a possible anatomical defect or immunodeficiency. Vaccination and surgical treatment of the anatomical defects may be important.


Assuntos
Meningites Bacterianas/microbiologia , Adolescente , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Lactente , Masculino , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/cirurgia , Recidiva , Fatores de Risco
20.
Eur J Pediatr ; 169(6): 759-62, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20177699

RESUMO

Kostmann disease is a rare autosomal recessive form of severe congenital neutropenia characterized by maturation arrest at the stage of promyelocytes/myelocytes in bone marrow with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/L and severe recurrent bacterial infections from early infancy. Kostmann disease is caused by homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1. Here, we report three patients with Kostmann disease who, besides recurrent infections, have developmental delay.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Deficiências do Desenvolvimento , Síndromes de Imunodeficiência , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/genética , Idade de Início , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/terapia , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/terapia , Síndrome , Turquia
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