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1.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907690

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.


Assuntos
Imunocompetência/genética , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Células Th17/imunologia , Fatores de Transcrição/genética , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Criança , Códon sem Sentido , Consanguinidade , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Síndrome de Job/sangue , Síndrome de Job/imunologia , Masculino , Linhagem , Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/imunologia , Células Th17/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Adulto Jovem , Dedos de Zinco/genética
2.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.


Assuntos
Regulação da Expressão Gênica/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Transcrição Genética/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Consanguinidade , Citocinas/imunologia , Citocinas/metabolismo , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Homozigoto , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Síndrome de Job/sangue , Síndrome de Job/imunologia , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem , Dedos de Zinco/genética
3.
J Allergy Clin Immunol ; 141(4): 1450-1458, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28916186

RESUMO

BACKGROUND: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. OBJECTIVES: This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. METHODS: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. RESULTS: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. CONCLUSIONS: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Síndromes de Imunodeficiência/mortalidade , Lactente , Irã (Geográfico) , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Masculino , Mutação/genética , Mutação/imunologia , Fenótipo , Estudos Retrospectivos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Análise de Sequência de DNA/métodos , Taxa de Sobrevida
4.
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
5.
J Autoimmun ; 37(1): 48-57, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21561736

RESUMO

Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48(-/-)). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48(-/-)) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48(-/-) animals, neither BALB.129CD48(-/-) mice nor B6 × BALB/c F1.129CD48(-/-) progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.


Assuntos
Antígenos CD/genética , Antígenos CD/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/genética , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Antígeno CD48 , Modelos Animais de Doenças , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Camundongos Knockout
6.
Curr Opin Allergy Clin Immunol ; 8(6): 515-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18978465

RESUMO

PURPOSE OF REVIEW: To describe novel immunological and molecular findings regarding early B cell development arrest resulting in autosomal recessive agammaglobulinemia. RECENT FINDINGS: Recently two different groups identified mutations in Ig beta, a component of the pre-B cell receptor, responsible for agammaglobulinemia in humans. These are the first two patients ever described with mutations in Ig beta. SUMMARY: These novel findings broaden the spectrum of genetic defects underlying this rare condition. This novel cause of agammaglobulinemia not only sheds light into early B cell development in humans but also sets the basis for potential alternative therapeutic approaches such as gene therapy.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Antígenos CD79/deficiência , Agamaglobulinemia/terapia , Animais , Subpopulações de Linfócitos B/patologia , Linfócitos B/patologia , Antígenos CD79/genética , Antígenos CD79/imunologia , Análise Mutacional de DNA , Genes Recessivos/imunologia , Terapia Genética/tendências , Humanos , Camundongos , Camundongos Knockout , Mutação
7.
J Allergy Clin Immunol ; 121(4): 940-46.e3, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18313126

RESUMO

BACKGROUND: Null mutations within the filaggrin gene (FLG) are associated with moderate-to-severe atopic eczema; their role in mild-to-moderate eczema in the general population is unknown. OBJECTIVE: We sought to investigate the significance of 5 common FLG null mutations in childhood atopic eczema in an unselected population cohort. METHODS: Eight hundred eleven English children aged 7 to 9 years were screened for FLG mutations. Eczema cases were defined by using United Kingdom diagnostic criteria and skin examination. Asthma and seasonal rhinitis cases were defined by parental questionnaire. Association between phenotype and genotype was investigated using Fisher exact test and logistic regression analysis. RESULTS: The 12-month period prevalence of atopic eczema was 24.2% (95% CI, 21.2% to 27.2%), with 96% (115/120) of cases having mild-to-moderate disease. The combined null genotype (carriage of > or = 1 FLG mutations) was significantly associated with atopic eczema (P = 1.2 x 10(-4)). The odds ratio (OR) for individuals carrying 2 null mutations was 26.9 (95% CI, 3.3-217.1), but heterozygote carriers showed no significant increase in risk (OR, 1.2; 95% CI, 0.7-1.9). Eight of 190 eczema cases (4.2%) carried 2 FLG null mutations and thus might be attributed to filaggrin deficiency. Asthma in the context of eczema showed significant association with the FLG null mutations (P = 7.1 x 10(-4)). There was no association of FLG with asthma independent of eczema (P = .15) and no association with seasonal rhinitis (P = .66). CONCLUSION: FLG null mutations are significantly associated with mild-to-moderate atopic eczema in childhood, with a recessive pattern of inheritance.


Assuntos
Eczema/genética , Hipersensibilidade Imediata/genética , Proteínas de Filamentos Intermediários/deficiência , Proteínas de Filamentos Intermediários/genética , Mutação , Asma/diagnóstico , Asma/genética , Asma/imunologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Eczema/diagnóstico , Eczema/imunologia , Feminino , Genes Recessivos/imunologia , Triagem de Portadores Genéticos , Humanos , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/imunologia , Proteínas de Filamentos Intermediários/fisiologia , Masculino , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/genética , Rinite Alérgica Sazonal/imunologia , Inquéritos e Questionários
8.
J Immunol ; 177(1): 255-67, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16785521

RESUMO

Self-reactive T cells that survive the process of positive and negative selection during thymocyte development represent potential effector cells against tumors that express these same self-Ags. We have previously shown that CD8+ T lymphocytes (T(CD8)) specific for an immunorecessive epitope, designated epitope V, from the SV40 large T Ag (Tag) escape thymic deletion in line SV11 Tag-transgenic mice. In contrast, these mice are tolerant to the three most dominant Tag epitopes. The majority of the residual epitope V-specific T(CD8) have a low avidity for the target epitope, but a prime/boost regimen can expand higher avidity clones in vivo. Whether higher avidity T(CD8) targeting this epitope are affected by Tag-expressing tumors in the periphery or can be recruited for control of tumor progression remains unknown. In the current study, we determined the fate of naive TCR-transgenic T(CD8) specific for Tag epitope V (TCR-V cells) following transfer into SV11 mice bearing advanced-stage choroid plexus tumors. The results indicate that TCR-V cells are rapidly triggered by the endogenous Tag and acquire effector function, but fail to accumulate within the tumors. Primary immunization enhanced TCR-V cell frequency in the periphery and promoted entry into the brain, but a subsequent booster immunization caused a dramatic accumulation of TCR-V T cells within the tumors and inhibited tumor progression. These results indicate that epitope V provides a target for CD8+ T cells against spontaneous tumors in vivo, and suggests that epitopes with similar properties can be harnessed for tumor immunotherapy.


Assuntos
Antígenos Transformantes de Poliomavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Imunização Secundária , Infecções por Polyomavirus/prevenção & controle , Infecções Tumorais por Vírus/prevenção & controle , Transferência Adotiva , Animais , Antígenos Transformantes de Poliomavirus/administração & dosagem , Antígenos Transformantes de Poliomavirus/biossíntese , Antígenos Transformantes de Poliomavirus/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/prevenção & controle , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Plexo Corióideo/imunologia , Plexo Corióideo/patologia , Testes Imunológicos de Citotoxicidade , Progressão da Doença , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/biossíntese , Epitopos de Linfócito T/genética , Feminino , Genes Recessivos/imunologia , Imunização Secundária/métodos , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estadiamento de Neoplasias , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/mortalidade , Infecções por Polyomavirus/patologia , Estrutura Terciária de Proteína/genética , Receptores de Antígenos de Linfócitos T/genética , Análise de Sobrevida , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/mortalidade , Infecções Tumorais por Vírus/patologia
9.
J Immunol ; 173(6): 4000-8, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15356149

RESUMO

We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-gammaR activity, their healthy heterozygous parents showed only partial IFN-gammaR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-gammaR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-gammaR2, an IFN-gammaR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-gammaR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-gammaR function by 48.7 +/- 5%, whereas fusion proteins with 278del2 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-gamma signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand.


Assuntos
Triagem de Portadores Genéticos , Homozigoto , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Deleção de Sequência , Linhagem Celular , Linhagem Celular Transformada , Feminino , Genes Dominantes/imunologia , Genes Recessivos/imunologia , Triagem de Portadores Genéticos/métodos , Humanos , Immunoblotting , Lactente , Interferon gama/metabolismo , Interferon gama/farmacologia , Interferon gama/fisiologia , Masculino , Complexo Mycobacterium avium/imunologia , Infecção por Mycobacterium avium-intracellulare/genética , Infecção por Mycobacterium avium-intracellulare/imunologia , Osteomielite/genética , Osteomielite/imunologia , Osteomielite/microbiologia , Receptores de Interferon/metabolismo , Receptores de Interferon/fisiologia , Proteínas Recombinantes de Fusão/deficiência , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/fisiologia , Deleção de Sequência/imunologia , Transfecção
10.
BMC Med Genet ; 4: 2, 2003 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-12542841

RESUMO

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.


Assuntos
Alelos , Doenças Transmissíveis/genética , Triagem de Portadores Genéticos , Antígenos HLA/genética , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/imunologia , Frequência do Gene/imunologia , Genes Dominantes/imunologia , Genes Recessivos/imunologia , Triagem de Portadores Genéticos/métodos , Predisposição Genética para Doença , Genética Populacional/métodos , Genética Populacional/estatística & dados numéricos , Genótipo , Homozigoto , Humanos , Imunidade Inata/genética , Modelos Genéticos , Modelos Imunológicos
11.
Clin Immunol ; 105(1): 75-80, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12483996

RESUMO

Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal recessive immunodeficiency disease characterized by initial involvement of cellular immunity and neurological manifestations with subsequent abnormalities of humoral immunity. The initial presentation and clinical course has varied widely in the relatively few published cases. The molecular basis has been reported in only 10 patients, precluding evaluation of phenotype-genotype relationships. We now report clinical, immunologic, and molecular findings in a new case of relatively early onset that emphasizes hypotonia and developmental delay as early manifestations. The patient carried two novel missense mutations (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation abolished enzyme activity while the Val217Ile mutation was without obvious effect and is therefore a normal variant. Such "normal" polymorphisms might be associated with a variable response to the immunosuppressive PNP inhibitors currently in clinical trials.


Assuntos
Insuficiência de Crescimento/genética , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/genética , Purina-Núcleosídeo Fosforilase/deficiência , Substituição de Aminoácidos , Animais , Sequência de Bases , Células COS , DNA/química , DNA/genética , Análise Mutacional de DNA , Insuficiência de Crescimento/imunologia , Evolução Fatal , Feminino , Genes Recessivos/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Lactente , Doenças do Sistema Nervoso/imunologia , Purina-Núcleosídeo Fosforilase/genética , Purina-Núcleosídeo Fosforilase/imunologia
12.
J Immunol ; 165(1): 42-8, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10861033

RESUMO

IL-4-producing gamma delta cells belong to a novel subset of gamma delta lymphocytes that expresses a very restricted repertoire of TCRs. To gain a deeper insight into the development and in vivo functions of these cells, we have analyzed the genetic control of their representation in the thymus. Using an intercross between C57BL/6 and DBA/2 mice we found two loci on chromosomes 13 and 17-named LadT1 and LadT2, respectively-with marked influence in their development. The LadT2 locus does not appear to be the MHC locus. The region identified on mouse chromosome 13 contains the structural genes for TCR gamma as well as the IL-9 gene, which has been suggested as a candidate gene influencing the complex pathogenesis of asthma.


Assuntos
Mapeamento Cromossômico , Interleucina-4/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Antígenos Thy-1/biossíntese , Timo/citologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Mapeamento Cromossômico/métodos , Cruzamentos Genéticos , Feminino , Genes Recessivos/imunologia , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T/imunologia , Marcadores Genéticos/imunologia , Haplótipos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Característica Quantitativa Herdável , Subpopulações de Linfócitos T/citologia , Timo/imunologia , Timo/metabolismo
13.
Autoimmunity ; 20(1): 25-32, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7578858

RESUMO

C57BL/6J (B6) mice homozygous for the viable motheaten (mev) mutation are short-lived and display severe immunodeficiency, autoimmunity and inflammatory disease. B6 mice doubly homozygous for the nude (nu) and beige (bg) mutations (nubg mice) are also short-lived and immunodeficient. Nevertheless, grafts of mev lympho-hematopoietic cells increased life expectancy of nubg recipients. Such [mev --> nubg] chimeras did not develop any mev-like inflammatory pathology but showed autoimmunity features, particularly hyperglobulinemia which, unlike the mev one, was due to IgG rather than IgM. Serological studies of [mev IgHb --> nubg Igha] chimeras surprisingly revealed the exclusive host B-cell origin of the IgG2a overproduced by these chimeras. Yet, about half of such chimera serum IgM being IgMb, mev B cells had actually engrafted the nubg hosts. Together with the lack of transfer of the inflammatory pathology, this suggests that a non-mev environment might succeed acting as a regulator of some mev-induced dysfunctions.


Assuntos
Genes Recessivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Isotipos de Imunoglobulinas/sangue , Animais , Anticorpos Antinucleares/sangue , Especificidade de Anticorpos/genética , Linfócitos B/metabolismo , DNA de Cadeia Simples/imunologia , Feminino , Imunoglobulina G/biossíntese , Isotipos de Imunoglobulinas/genética , Imunoglobulina M/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Nus , Quimera por Radiação
14.
Immunology ; 75(4): 688-92, 1992 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1592441

RESUMO

The new mutation at the lpr locus, lprcg, induces massive lymphoproliferation characterized by the selective expansion of CD4-, CD8-, B220+, Thy-1+ cells or double-negative T lymphocytes and production of autoantibodies as does lpr. The thymus is necessary for the induction of anomalous double-negative T lymphocytes and autoimmune symptoms by lpr. To determine whether or not the thymus is also indispensable to expression of the function of lrpcg, lprcg homozygous athymic nude mice (lprcg/lprcg nu/nu; lprcg nudes) were constructed by crossing CBA/KlJms-lprcg/lprcg (CBA-lprcg) and DDD/l-nu/nu mice and observed for lymphoid organ hyperplasia and autoantibody production with or without thymus grafts from various strains of mice including CBA-lprcg. Neither lymphoproliferation nor significantly increased production of autoantibodies was observed in unmanipulated lprcg nudes. In contrast, thymus grafts of both +/+ and lprcg/lprcg genotypes caused lymphoid organ hyperplasia composed of anomalous double-negative T lymphocytes and significantly augmented the production of antibodies against single-stranded DNA (ssDNA). Interestingly, serum Ig and anti-ssDNA antibody levels rose in response to thymus grafts only in IgG but not in IgM classes. These results indicate that the thymus plays a crucial role in the induction of abnormal T-cell differentiation by lprcg and that thymic genotype is irrelevant.


Assuntos
Doenças Autoimunes/imunologia , Genes Recessivos/imunologia , Doenças Linfáticas/imunologia , Timo/imunologia , Animais , Anticorpos Antinucleares/análise , Antígenos de Superfície/análise , DNA de Cadeia Simples/imunologia , Imunoglobulina G/análise , Imunoglobulina M/análise , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos CBA , Camundongos Endogâmicos
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