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1.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive. CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

2.
Front Immunol ; 9: 782, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713328

RESUMO

Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PID). T-cell receptor excision circle (TREC) copy number analysis is an efficient tool for population-based newborn screening (NBS) for SCID and other T cell lymphopenias. We sought to assess the incidence of SCID among Saudi newborn population and examine the feasibility of using targeted next generation sequencing PID gene panel (T-NGS PID) on DNA isolated from dried blood spots (DBSs) in routine NBS programs as a mutation screening tool for samples with low TREC count. Punches from 8,718 DBS collected on Guthrie cards were processed anonymously for the TREC assay. DNA was extracted from samples with confirmed low TREC count, then screened for 22q11.2 deletion syndrome by real-time polymerase chain reaction and for mutations in PID-related genes by T-NGS PID panel. Detected mutations were confirmed by Sanger sequencing. Sixteen out of the 8,718 samples were confirmed to have low TREC copy number. Autosomal recessive mutations in AK2, JAK3, and MTHFD1 were confirmed in three samples. Two additional samples were positive for the 22q11.2 deletion syndrome. In this study, we provide evidence for high incidence of SCID among Saudi population (1/2,906 live births) and demonstrate the feasibility of using T-NGS PID panel on DNA extracted from DBSs as a new reliable, rapid, and cost-effective mutation screening method for newborns with low TREC assay, which can be implemented as part of NBS programs for SCID.

3.
Curr Diabetes Rev ; 14(5): 427-433, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28677496

RESUMO

BACKGROUND: Metabolic syndrome is associated with increased risk for both type 2 diabetes and cardiovascular disease. Development of these pathologies is associated with the disorders of lipid and lipoprotein metabolism. Dyslipidemia leads to the overproduction of potentially atherogenic lipid and lipoproteins. Furthermore, there is a decrease in the levels of high-density lipoproteins and an increase in the levels of remnant and small dense LDL particles. CONCLUSION: In the current review, we have discussed the pathophysiology of lipoprotein biosynthesis and metabolism in the metabolic syndrome. Finally, we describe regulation of lipoprotein metabolism which may be used as a potential target for treating dyslipidemia in metabolic syndrome.


Assuntos
Dislipidemias/sangue , Lipoproteínas/sangue , Síndrome Metabólica/sangue , Animais , Biomarcadores/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Regulação da Expressão Gênica , Humanos , Hipolipemiantes/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , MicroRNAs/genética , MicroRNAs/metabolismo
4.
J Clin Immunol ; 37(6): 575-581, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28741180

RESUMO

INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.


Assuntos
Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Síndromes de Imunodeficiência/genética , Microcefalia/genética , Mutação/genética , Isoformas de Proteínas/genética , Sítios de Splice de RNA/genética , Adolescente , Adulto , Processamento Alternativo , Criança , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Irmãos
6.
Clin Immunol ; 178: 39-44, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27890707

RESUMO

BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/etiologia , Neoplasias das Glândulas Suprarrenais/virologia , Criança , Pré-Escolar , Colangite Esclerosante/etiologia , Consanguinidade , Eczema/etiologia , Eosinofilia/etiologia , Infecções por Vírus Epstein-Barr/etiologia , Esofagite/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpes Simples/etiologia , Humanos , Síndrome de Job/complicações , Síndrome de Job/imunologia , Síndrome de Job/terapia , Leiomioma/etiologia , Leiomioma/virologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/patologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/virologia , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/virologia , Linhagem , Recidiva , Infecções Estafilocócicas/etiologia , Adulto Jovem
7.
Cell Rep ; 17(12): 3206-3218, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-28009290

RESUMO

Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Timócitos/imunologia , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/terapia , Regulação da Expressão Gênica/imunologia , Rearranjo Gênico/genética , Humanos , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Células Th17/efeitos dos fármacos , Células Th17/imunologia
8.
J Allergy Clin Immunol ; 137(6): 1780-1787, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26915675

RESUMO

BACKGROUND: Molecular genetics techniques are an essential diagnostic tool for primary immunodeficiency diseases (PIDs). The use of next-generation sequencing (NGS) provides a comprehensive way of concurrently screening a large number of PID genes. However, its validity and cost-effectiveness require verification. OBJECTIVES: We sought to identify and overcome complications associated with the use of NGS in a comprehensive gene panel incorporating 162 PID genes. We aimed to ascertain the specificity, sensitivity, and clinical sensitivity of the gene panel and its utility as a diagnostic tool for PIDs. METHODS: A total of 162 PID genes were screened in 261 patients by using the Ion Torrent Proton NGS sequencing platform. Of the 261 patients, 122 had at least 1 known causal mutation at the onset of the study and were used to assess the specificity and sensitivity of the assay. The remaining samples were from unsolved cases that were biased toward more phenotypically and genotypically complicated cases. RESULTS: The assay was able to detect the mutation in 117 (96%) of 122 positive control subjects with known causal mutations. For the unsolved cases, our assay resulted in a molecular genetic diagnosis for 35 of 139 patients. Interestingly, most of these cases represented atypical clinical presentations of known PIDs. CONCLUSIONS: The targeted NGS PID gene panel is a sensitive and cost-effective diagnostic tool that can be used as a first-line molecular assay in patients with PIDs. The assay is an alternative choice to the complex and costly candidate gene approach, particularly for patients with atypical presentation of known PID genes.


Assuntos
Marcadores Genéticos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Biologia Computacional , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Síndromes de Imunodeficiência/imunologia , Mutação , Polimorfismo de Nucleotídeo Único , Fluxo de Trabalho
9.
Pediatr Transplant ; 19(6): 634-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26073206

RESUMO

HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/terapia , Ligante de CD40/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Marcadores Genéticos , Doença Enxerto-Hospedeiro , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/mortalidade , Lactente , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento
10.
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
11.
J Immunol ; 194(2): 790-4, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25472997

RESUMO

The Tcra/Tcrd locus undergoes V-Dδ-Jδ rearrangement in CD4(-)CD8(-) thymocytes to form the TCRδ chain of the γδ TCR and V-Jα rearrangement in CD4(+)CD8(+) thymocytes to form the TCRα-chain of the αß TCR. Most V segments in the locus participate in V-Jα rearrangement, but only a small and partially overlapping subset participates in V-Dδ-Jδ rearrangement. What specifies any particular Tcra/Tcrd locus V gene segment as a Vδ, a Vα, or both is currently unknown. We tested the hypothesis that V segment usage is specified by V segment promoter-dependent chromatin accessibility in developing thymocytes. TRAV15/DV6 family V gene segments contribute to both the Tcrd and the Tcra repertoires, whereas TRAV12 family V gene segments contribute almost exclusively to the Tcra repertoire. To understand whether the TRAV15/DV6 promoter region specifies TRAV15/DV6 as a Vδ, we used gene targeting to replace the promoter region of a TRAV12 family member with one from a TRAV15/DV6 family member. The TRAV15/DV6 promoter region conferred increased germline transcription and histone modifications to TRAV12 in double-negative thymocytes and caused a substantial increase in usage of TRAV12 in Tcrd recombination events. Our results demonstrate that usage of TRAV15/DV6 family V gene segments for Tcrd recombination in double-negative thymocytes is regulated, at least in part, by intrinsic features of TRAV15/DV6 promoters, and argue that Tcra/Tcrd locus Vδ gene segments are defined by their local chromatin accessibility in CD4(-)CD8(-) thymocytes.


Assuntos
Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T , Loci Gênicos , Regiões Promotoras Genéticas , Animais , Marcação de Genes , Camundongos , Timócitos/citologia
12.
Mod Rheumatol ; 24(4): 690-3, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24517560

RESUMO

Hyperimmunoglobulin E syndrome (HIES) is a primary immunodeficiency disorder with multisystem abnormalities including the vascular system. We report a child with autosomal recessive (AR)-HIES secondary to dedicator of cytokinesis 8 (DOCK8) deficiency who developed critical aortic aneurysm involving the ascending aorta and aortic arch with narrowing of descending aorta that was successfully managed surgically. This report highlights the underrecognized and serious complication of DOCK8 deficiency that could contribute to significant morbidity and mortality in such patients.


Assuntos
Aneurisma Aórtico/complicações , Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndrome de Job/complicações , Aneurisma Aórtico/cirurgia , Criança , Humanos , Masculino , Resultado do Tratamento
13.
J Clin Immunol ; 33(8): 1325-35, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24122029

RESUMO

PURPOSE: Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency with few reported cases. In this study, we further characterize the clinical, immunological, and molecular profiles of the disease in a cohort of 11 patients. METHODS: Molecular genetic analysis and a comprehensive clinical review of patients diagnosed with HIGM3 at our tertiary care center from 1994 to 2011 were undertaken. RESULTS: Eleven patients from seven families were enrolled. The patients had a median age of 9 years [ranging from 2 to 22 years old]. All 11 patients had recurrent chest infections at presentation. Pneumocystis jiroveci pneumonia was confirmed in three patients. Five patients had sclerosing cholangitis, and five patients had Cryptosporidium isolated from their stool. Six patients had nasal and sinus infections, and two of these patients had destructive nasal fungal infections. Eight patients had neutropenia. All of the patients had low IgG and normal or high IgM levels. IgA was undetectable in all but three patients. Two novel mutations were found: a splice site for intron 3 and a missense mutation located in the coding region of exon 3. Two patients underwent successful stem cell transplantation from a matched donor. Four patients are doing well on prophylaxis; two are very sick, one with protracted diarrhea and persistent Cryptosporidium and the other with neurological complications. Three patients died early in life as a result of severe sepsis. CONCLUSIONS: To our knowledge, this report provides the largest cohort of patients with this disease with a very long follow-up period. Our cohort showed variable disease severity


Assuntos
Antígenos CD40/deficiência , Síndrome de Imunodeficiência com Hiper-IgM/genética , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Antígenos CD40/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/microbiologia , Síndromes de Imunodeficiência/microbiologia , Lactente , Masculino , Mutação , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Estudos Retrospectivos , Adulto Jovem
14.
J Clin Immunol ; 33(4): 871-5, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23371790

RESUMO

INTRODUCTION: Complement deficiencies are rare primary immunodeficiency disorders, the diagnosis of which is often underestimated. Only a small number of molecular studies have been carried out for the characterization of the underlying genetic defects in these cases. PURPOSE: Reporting the first family from the Arabian Gulf region with multiple members affected by meningococcemia and abscent serum complement 5 (C5). We tried to correlate clinical, biochemical and molecular genetics features of this family. METHODS: Determination of the serum level of all complement proteins including the terminal cascade (C5-9), followed by mutation analysis on DNA extracted from fresh blood samples of each alive family member. RESULTS: Molecular studies showed a homozygous nonsense mutation in exon 1, with the change of cytosine to thymine at position 55 (55C > T) leading to change of the glutamine amino acid at position 19 to a stop codon (Q19X), and serologically absence of C5 in the serum. A similar but compound heterozygous mutation has been reported in one African-American family. previously. CONCLUSION: Characterization of the underlying mutations in C5 deficient families is important, to understand this uncommon complement deficiency, and try to elucidate structure-function relationships in the C5 gene. This report also highlights the importance of complement screening in cases of sporadic meningococcal Infections, especially in communities with high prevalence of consanguineous marriages, which will ensure timely and adequate clinical interventions.


Assuntos
Complemento C5/deficiência , Síndromes de Imunodeficiência/genética , Infecções Meningocócicas/genética , Neisseria meningitidis/imunologia , Pré-Escolar , Complemento C5/genética , Consanguinidade , Análise Mutacional de DNA , Genótipo , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Masculino , Infecções Meningocócicas/diagnóstico , Infecções Meningocócicas/etiologia , Infecções Meningocócicas/imunologia , Linhagem , Arábia Saudita , Deleção de Sequência/genética , Relação Estrutura-Atividade
16.
J Clin Immunol ; 33(1): 55-67, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22968740

RESUMO

PURPOSE: Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis. METHODS: Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.


Assuntos
Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/química , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hospitais Especializados , Síndrome de Job/genética , Síndrome de Job/imunologia , Adolescente , Criança , Pré-Escolar , Códon sem Sentido/genética , Feminino , Genes Recessivos/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Imunoglobulina E/efeitos adversos , Imunoglobulina E/sangue , Incidência , Síndrome de Job/epidemiologia , Masculino , Arábia Saudita/epidemiologia , Prevenção Secundária
17.
J Immunol ; 189(9): 4459-69, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23024272

RESUMO

The closely linked human IL-3 and GM-CSF genes are tightly regulated and are expressed in activated T cells and mast cells. In this study, we used transgenic mice to study the developmental regulation of this locus and to identify DNA elements required for its correct activity in vivo. Because these two genes are separated by a CTCF-dependent insulator, and the GM-CSF gene is regulated primarily by its own upstream enhancer, the main objective in this study was to identify regions of the locus required for correct IL-3 gene expression. We initially found that the previously identified proximal upstream IL-3 enhancers were insufficient to account for the in vivo activity of the IL-3 gene. However, an extended analysis of DNase I-hypersensitive sites (DHSs) spanning the entire upstream IL-3 intergenic region revealed the existence of a complex cluster of both constitutive and inducible DHSs spanning the -34- to -40-kb region. The tissue specificity of these DHSs mirrored the activity of the IL-3 gene, and included a highly inducible cyclosporin A-sensitive enhancer at -37 kb that increased IL-3 promoter activity 40-fold. Significantly, inclusion of this region enabled correct in vivo regulation of IL-3 gene expression in T cells, mast cells, and myeloid progenitor cells.


Assuntos
Elementos Facilitadores Genéticos/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Interleucina-3/biossíntese , Interleucina-3/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Desoxirribonuclease I/genética , Elementos Facilitadores Genéticos/genética , Loci Gênicos/imunologia , Humanos , Células Jurkat , Camundongos , Camundongos Transgênicos , Distribuição Tecidual/genética , Distribuição Tecidual/imunologia
18.
J Immunol ; 179(4): 2228-34, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17675483

RESUMO

CD1d-restricted NKT cells that express an invariant Valpha14 TCR represent a subset of T cells implicated in the regulation of several immune responses, including autoimmunity, infectious disease, and cancer. Proper rearrangement of Valpha14 with the Jalpha18 gene segment in immature thymocytes is a prerequisite to the production of a TCR that can be subsequently positively selected by CD1d/self-ligand complexes in the thymus and gives rise to the NKT cell population. We show here that Valpha14 to Jalpha rearrangements are temporally regulated during ontogeny providing a molecular explanation to their late appearance in the thymus. Using mice deficient for the transcription factor RORgamma and the germline promoters T early-alpha and Jalpha49, we show that developmental constraints on both Valpha and Jalpha usage impact NKT cell development. Finally, we demonstrate that rearrangements using Valpha14 and Jalpha18 occur normally in the absence of FynT, arguing that the effect of FynT on NKT cell development occurs subsequent to alpha-chain rearrangement. Altogether, this study provides evidence that there is no directed rearrangement of Valpha14 to Jalpha18 segments and supports the instructive selection model for NKT cell selection.


Assuntos
Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/imunologia , Células Matadoras Naturais/imunologia , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Antígenos CD1/imunologia , Antígenos CD1d , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/genética , Camundongos , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/imunologia , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/imunologia
19.
Proc Natl Acad Sci U S A ; 104(3): 903-7, 2007 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-17210914

RESUMO

During the recombination of variable (V) and joining (J) gene segments at the T cell receptor alpha locus, a ValphaJalpha joint resulting from primary rearrangement can be replaced by subsequent rounds of secondary rearrangement that use progressively more 5' Valpha segments and progressively more 3' Jalpha segments. To understand the mechanisms that target secondary T cell receptor alpha recombination, we studied the behavior of a T cell receptor alpha allele (HYalpha) engineered to mimic a natural primary rearrangement of TRAV17 to Jalpha57. The introduced ValphaJalpha segment was shown to provide chromatin accessibility to Jalpha segments situated within several kilobases downstream and to suppress germ-line Jalpha promoter activity and accessibility at greater distances. As a consequence, the ValphaJalpha segment directed secondary recombination events to a subset of Jalpha segments immediately downstream from the primary rearrangement. The data provide the mechanistic basis for a model of primary and secondary T cell receptor alpha recombination in which recombination events progress in multiple small steps down the Jalpha array.


Assuntos
Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Recombinação Genética/genética , Alelos , Animais , Camundongos
20.
J Exp Med ; 202(4): 467-72, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16087716

RESUMO

Murine Tcrd and Tcra gene segments reside in a single genetic locus and undergo recombination in CD4- CD8- (double negative [DN]) and CD4+ CD8+ (double positive [DP]) thymocytes, respectively. TcraTcrd locus variable gene segments are subject to complex regulation. Only a small subset of approximately 100 variable gene segments contributes substantially to the adult TCRdelta repertoire. Moreover, although most contribute to the TCRalpha repertoire, variable gene segments that are Jalpha proximal are preferentially used during primary Tcra recombination. We investigate the role of local chromatin accessibility in determining the developmental pattern of TcraTcrd locus variable gene segment recombination. We find variable gene segments to be heterogeneous with respect to acetylation of histones H3 and H4. Those that dominate the adult TCRdelta repertoire are hyperacetylated in DN thymocytes, independent of their position in the locus. Moreover, proximal variable gene segments show dramatic increases in histone acetylation and germline transcription in DP thymocytes, a result of super long-distance regulation by the Tcra enhancer. Our results imply that differences in chromatin accessibility contribute to biases in TcraTcrd locus variable gene segment recombination in DN and DP thymocytes and extend the distance over which the Tcra enhancer can regulate chromatin structure to a remarkable 525 kb.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/genética , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/genética , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T/genética , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T/genética , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T/genética , Acetilação , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Elementos Facilitadores Genéticos/genética , Elementos Facilitadores Genéticos/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/imunologia , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T/imunologia , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T/imunologia , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T/imunologia , Histonas/imunologia , Camundongos , Camundongos Knockout , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologia , Recombinação Genética/genética , Recombinação Genética/imunologia , Timo/citologia , Timo/imunologia , Transcrição Genética/genética , Transcrição Genética/imunologia
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