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3.
Front Immunol ; 9: 1049, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963038

RESUMO

B cell expansion with NF-κB and T cell anergy (BENTA) is a rare primary immunodeficiency disorder caused by mutations in the CARD11 gene and results in constitutive NF-κB activation in B and T cells. Affected patients present with polyclonal expansion of B cells at an early age with splenomegaly, lymphadenopathy, and mild autoimmunity. Here, we discuss four BENTA cases with unusual clinical manifestations not previously reported. All patients showed previously reported gain-of-function mutations (G123S, G123D, and C49Y) in the CARD11 gene. Severe autoimmune manifestations were noted for the first time in all our patients.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Linfócitos B/citologia , Proteínas Adaptadoras de Sinalização CARD/genética , Anergia Clonal , Guanilato Ciclase/genética , NF-kappa B/metabolismo , Linfócitos T/patologia , Síndrome Linfoproliferativa Autoimune/diagnóstico , Pré-Escolar , Feminino , Mutação com Ganho de Função , Humanos , Índia , Lactente , Masculino , Transdução de Sinais , Linfócitos T/citologia , Sequenciamento Completo do Genoma
4.
Clin Exp Dermatol ; 43(8): 913-916, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29908030

RESUMO

Ras-associated autoimmune leucoproliferative disorder (RALD) is a nonmalignant syndrome associated with somatic KRAS mutations. We report a patient with RALD and cutaneous lesions, the first such case reported, to our knowledge. An 8-year-old boy presented with erythematous plaques on his face and body, along with lymphadenopathies and spleen enlargement without systemic symptoms. An increased number of monocytes were found in skin biopsy, peripheral blood and bone marrow (BM). Juvenile myelomonocytic leukaemia (JMML) was suspected. Genetic study using peripheral blood showed no mutations in the KRAS, PTPN11, NRAS, CBL or BCR-ABL genes, but bone marrow analysis revealed a mutation (p-G12S/c.34 G>A) in the KRAS gene. The karyotype was normal. No KRAS mutations were found using molecular analysis of saliva. The diagnosis of RALD was proposed. The differential diagnosis between RALD and JMML is challenging because there are no established criteria to differentiate between them. The clinical course of RALD is uncertain, so long-term follow-up is recommended.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Proteínas Proto-Oncogênicas p21(ras) , Dermatopatias/etiologia , Pele/patologia , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/patologia , Biópsia , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Genes ras , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética
5.
Gene ; 672: 45-49, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-29864493

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly and lymphadenopathy along with hemocytopenia. This case report describes a 10-year-old boy presenting with signs of autoimmune disease, splenomegaly, hepatomegaly and resistant hemocytopenia. Sirolimus controlled the relapsed thrombocytopenia after splenectomy. Sequencing of the FAS gene identified two spontaneous heterozygous mutations (c.234 T > G, p.D78E) (c.236dupA, p.P80Tfs*26). The boy's homozygous missense variation (c.2588G > A, p.G863D) (rs140184929) in UNC13D gene had been identified as being related to familial hemophagocytic lymphohistiocytosis (FHL). TCRαß + CD4/CD8 double-negative T cells (markers of ALPS) were not significantly increased from the outset. Elevated cytokines, such as interferon (IFN)-γ, interleukin (IL)-6 and tumor necrosis factor α decreased to normal levels after splenectomy whereas IL-10 remained high. Immunological analysis of the patient revealed a marked depletion of forkhead-box P3+ expressing regulatory T cells (Treg) and Th17 cells. The obtained data demonstrate that mutations to FAS and UNC13D which result in overwhelming T-cell and macrophage activation, one associated with inhibited Treg cell development and a severe ALPS-like symptom. Therefore, we propose that variations of UND13D may be a risk factor of ALPS development.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Proteínas de Membrana/genética , Receptor fas/genética , Síndrome Linfoproliferativa Autoimune/genética , Sequência de Bases , Criança , China , Análise Mutacional de DNA , Epistasia Genética , Estudos de Associação Genética , Humanos , Masculino
6.
J Leukoc Biol ; 103(3): 501-508, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29345341

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Consanguinidade , Mutação , Índice de Gravidade de Doença , Receptor fas/deficiência , Receptor fas/genética , Humanos , Receptor fas/imunologia
8.
Pediatr Blood Cancer ; 65(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29271561

RESUMO

Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy.


Assuntos
Adenosina Desaminase/deficiência , Síndrome Linfoproliferativa Autoimune , Exoma , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Livedo Reticular , Mutação Puntual , Vasculite , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/enzimologia , Síndrome Linfoproliferativa Autoimune/genética , Pré-Escolar , Feminino , Humanos
9.
J Allergy Clin Immunol ; 142(2): 595-604.e16, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29155103

RESUMO

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically. OBJECTIVE: We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype. METHODS: Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported. RESULTS: The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells. CONCLUSIONS: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Proteínas de Ligação a DNA/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Linfócitos T/imunologia , Anticorpos Antinucleares/sangue , Síndrome Linfoproliferativa Autoimune/diagnóstico , Autoimunidade , Morte Celular , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Pré-Escolar , Feminino , Heterozigoto , Humanos , Recém-Nascido , Ativação Linfocitária , Masculino , Mutação/genética , Linhagem , Receptores de Antígenos de Linfócitos T/genética , Irmãos , Transdução de Sinais , Sequenciamento Completo do Exoma
10.
J Immunol ; 200(1): 110-118, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29187589

RESUMO

Understanding the control of Ag restimulation-induced T cell death (RICD), especially in cancer immunotherapy, where highly proliferating T cells will encounter potentially large amounts of tumor Ags, is important now more than ever. It has been known that growth cytokines make T cells susceptible to RICD, but the precise molecular mediators that govern this in T cell subsets is unknown until now. STAT proteins are a family of transcription factors that regulate gene expression programs underlying key immunological processes. In particular, STAT5 is known to favor the generation and survival of memory T cells. In this study, we report an unexpected role for STAT5 signaling in the death of effector memory T (TEM) cells in mice and humans. TEM cell death was prevented with neutralizing anti-IL-2 Ab or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives RICD in TEM cells. Moreover, we identified a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to Stat5b-/- mice, this patient exhibited increased CD4+ TEM cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes in patient T cells upon IL-2 stimulation. Notably, CD4+ TEM cells from the patient were strikingly resistant to cell death by in vitro TCR restimulation, a finding that was recapitulated in Stat5b-/- mice. Hence, STAT5B is a crucial regulator of RICD in memory T cells in mice and humans.


Assuntos
Apoptose , Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Sobrevivência Celular , Fator de Transcrição STAT5/metabolismo , Animais , Anticorpos Neutralizantes/metabolismo , Síndrome Linfoproliferativa Autoimune/genética , Células Cultivadas , Feminino , Humanos , Memória Imunológica , Interleucina-2/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação de Sentido Incorreto/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais , Transcrição Genética
11.
Curr Opin Immunol ; 49: 79-86, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29073495

RESUMO

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. This clinical entity was recognized in the mid 60s and its genetic etiology was described in 1995 by the discovery of the FAS gene mutations. This was the first description of a monogenic cause of autoimmunity but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic causes of ALPS such as somatic mutations of RAS or the recently described CTLA-4 insufficiency. The recognition of these genetic diseases brought new information on the regulation of the adaptive immune responses and uncovered new therapeutical targets. Finally, the deciphering the role of somatic mutations may pave the way to the understanding of more common autoimmune diseases.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos/imunologia , Receptor fas/genética , Animais , Apoptose/genética , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Autoimunidade , Antígeno CTLA-4/genética , Proliferação de Células , Diagnóstico Diferencial , Genes ras/genética , Humanos , Terapia de Alvo Molecular
12.
Orv Hetil ; 158(32): 1269-1276, 2017 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-28780879

RESUMO

INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Síndrome Linfoproliferativa Autoimune/tratamento farmacológico , Danazol/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Transtornos do Crescimento/induzido quimicamente , Adolescente , Angioedemas Hereditários/genética , Síndrome Linfoproliferativa Autoimune/genética , Criança , Proteína Inibidora do Complemento C1/genética , Danazol/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco
13.
N Z Vet J ; 65(6): 327-331, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28814155

RESUMO

AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as carriers of the variant allele should be desexed and not used for breeding. Results support the need for further investigations of the true frequency of the FASLG variant allele and occurrence of FALPS in the wider population of BSH cats in New Zealand.


Assuntos
Síndrome Linfoproliferativa Autoimune/veterinária , Doenças do Gato/genética , Proteína Ligante Fas , Animais , Síndrome Linfoproliferativa Autoimune/epidemiologia , Síndrome Linfoproliferativa Autoimune/genética , Doenças do Gato/epidemiologia , Gatos , Proteína Ligante Fas/genética , Feminino , Genótipo , Endogamia , Masculino , Nova Zelândia/epidemiologia
14.
Allergy Asthma Proc ; 38(4): 317-321, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28668112

RESUMO

A case of autoimmune lymphoproliferative syndrome (ALPS) was presented, followed by a discussion of the clinical characteristics, pathophysiology, diagnosis, and management of this disease. Clinical pearls and pitfalls are emphasized for the use of the practicing allergist and the fellow in-training. The diagnosis of ALPS was guided by published criteria. A careful history and workup were needed to exclude other possible etiologies for the patient's symptoms and physical findings. ALPS often carries significant morbidity and is best managed through a multidisciplinary approach.


Assuntos
Doenças Autoimunes/diagnóstico , Síndrome Linfoproliferativa Autoimune/diagnóstico , Doenças Autoimunes/epidemiologia , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/terapia , Análise Mutacional de DNA , Diagnóstico Diferencial , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Fenótipo , Valor Preditivo dos Testes , Adulto Jovem , Receptor fas/genética
15.
Clin Immunol ; 183: 17-23, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28668589

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations.


Assuntos
Processamento Alternativo/genética , Síndrome Linfoproliferativa Autoimune/genética , Receptor fas/genética , Síndrome Linfoproliferativa Autoimune/sangue , Western Blotting , Consanguinidade , Proteína Ligante Fas/sangue , Mutação em Linhagem Germinativa , Humanos , Lactente , Interleucina-10/sangue , Líbia , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Tunísia , Receptor fas/sangue
16.
Clin Immunol ; 181: 32-42, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28579554

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options.


Assuntos
Apoptose/genética , Síndrome Linfoproliferativa Autoimune/genética , Fator de Transcrição STAT3/genética , Compostos de Bifenilo , Hidroxitolueno Butilado/análogos & derivados , Estudos de Casos e Controles , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Família , Proteína Ligante Fas/metabolismo , Feminino , Perfilação da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Immunoblotting , Imunofenotipagem , Leucócitos Mononucleares , Linfócitos , Nitrofenóis , Piperazinas , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Sulfonamidas , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Receptor fas/metabolismo
17.
Clin Exp Immunol ; 189(3): 310-317, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28500641

RESUMO

Ras-associated lymphoproliferative disease (RALD) is an autoimmune lymphoproliferative syndrome (ALPS)-like disease caused by mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) or neuroblastoma RAS viral (V-Ras) oncogene homologue (NRAS). The immunological phenotype and pathogenesis of RALD have yet to be studied extensively. Here we report a thorough immunological investigation of a RALD patient with a somatic KRAS mutation. Patient lymphocytes were analysed for phenotype, immunoglobulin levels and T cell proliferation capacity. T and B cell receptor excision circles (TREC and KREC, respectively), markers of naive T and B cell production, were measured serially for 3 years. T and B cell receptor repertoires were studied using both traditional assays as well as next-generation sequencing (NGS). TREC and KREC declined dramatically with time, as did T cell receptor diversity. NGS analysis demonstrated T and B clonal expansions and marked restriction of T and B cell receptor repertoires compared to healthy controls. Our results demonstrate, at least for our reported RALD patient, how peripheral T and B clonal expansions reciprocally limit lymphocyte production and restrict the lymphocyte receptor repertoire in this disease. Decreased naive lymphocyte production correlated with a clinical deterioration in our patient's immune status, suggesting that TREC and KREC may be used as an aid in monitoring disease progression. Both the methodologies used here and the conclusions regarding immune homeostasis may be applicable to the research of ALPS and other immune dysregulation syndromes.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos B/fisiologia , Genes ras , Mutação , Linfócitos T/fisiologia , Linfócitos B/imunologia , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia
18.
Scand J Immunol ; 85(6): 406-416, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28349581

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease, which is characterized by non-malignant autoimmune lymphoproliferation. TCF1 is a key effector in the canonical Wnt/ß-catenin pathway, regulating the development, activation and function of T cells. In this study, we aimed to explore the potential role of TCF1 in the development of ALPS-like phenotypes of lpr/lpr mice. We acquired TCF1-/- lpr/lpr double mutant mice by crossing TCF1 deficiency mice with lpr/lpr mice. Splenocyte compositions, serum cytokines levels, antidsDNA antibody production and kidney pathology were examined in the TCF1-/- lpr/lpr mice. With these examinations, we revealed that TCF1 deficiency relieved most manifestations of ALPS-like phenotype, which were caused by Fas mutation in TCF1-/- lpr/lpr mice. Splenocyte total numbers and compositions were downregulated to the similar levels with wildtype mice. TE and TEM cells were decreased in TCF1-/- lpr/lpr compared with lpr/lpr mice. The levels of autoantibodies and proinflammatory factors in serum, and the histopathology changes and the relative mRNA levels of proinflammatory factors in kidney all displayed parallel tendency in TCF1-/- lpr/lpr mice. Our study demonstrated that TCF1 deficiency ameliorated the ALPS-like phenotypes of TCF1-/- lpr/lpr mice, which might indicate a potential therapeutic direction for ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Mutação , Receptor fas/genética , Animais , Autoanticorpos/sangue , Síndrome Linfoproliferativa Autoimune/metabolismo , Síndrome Linfoproliferativa Autoimune/patologia , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Predisposição Genética para Doença/genética , Genótipo , Fator 1-alfa Nuclear de Hepatócito/deficiência , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Microscopia de Fluorescência , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Baço/patologia , Receptor fas/metabolismo
19.
J Allergy Clin Immunol ; 139(6): 1914-1922, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27845235

RESUMO

BACKGROUND: Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. OBJECTIVE: The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. METHODS: Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. RESULTS: A de novo heterozygous frameshift mutation of TNF-α-induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). CONCLUSION: Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Células Cultivadas , Mutação em Linhagem Germinativa , Haploinsuficiência , Humanos , Lactente , Leucócitos Mononucleares/imunologia , Masculino , NF-kappa B/imunologia , Fenótipo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia
20.
Mamm Genome ; 28(1-2): 47-55, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27770190

RESUMO

British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.


Assuntos
Apoptose/genética , Síndrome Linfoproliferativa Autoimune/genética , Proteína Ligante Fas/genética , Receptor fas/genética , Animais , Síndrome Linfoproliferativa Autoimune/patologia , Gatos , Códon sem Sentido/genética , Mutação da Fase de Leitura/genética , Genoma , Humanos , Linfócitos/patologia , Mutação , Sequenciamento Completo do Genoma
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