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1.
Immunity ; 52(2): 313-327.e7, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32049052

RESUMO

T cell responses upon infection display a remarkably reproducible pattern of expansion, contraction, and memory formation. If the robustness of this pattern builds entirely on signals derived from other cell types or if activated T cells themselves contribute to the orchestration of these population dynamics-akin to bacterial quorum regulation-is unclear. Here, we examined this question using time-lapse microscopy, genetic perturbation, bioinformatic predictions, and mathematical modeling. We found that ICAM-1-mediated cell clustering enabled CD8+ T cells to collectively regulate the balance between proliferation and apoptosis. Mechanistically, T cell expressed CD80 and CD86 interacted with the receptors CD28 and CTLA-4 on neighboring T cells; these interactions fed two nested antagonistic feedback circuits that regulated interleukin 2 production in a manner dependent on T cell density as confirmed by in vivo modulation of this network. Thus, CD8+ T cell-population-intrinsic mechanisms regulate cellular behavior, thereby promoting robustness of population dynamics.

2.
Clin Immunol ; 210: 108316, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770611

RESUMO

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

3.
Clin Immunol ; 201: 30-34, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776520

RESUMO

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.


Assuntos
Infecções por Citomegalovirus/imunologia , Doenças Hematológicas/imunologia , Linfócitos Intraepiteliais/imunologia , Imunodeficiência Combinada Severa/imunologia , Humanos , Contagem de Linfócitos
4.
Sci Transl Med ; 10(429)2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467301

RESUMO

Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617F mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Hematológicas/metabolismo , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/metabolismo , Animais , Antígeno B7-H1/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Transformação Celular Neoplásica , Neoplasias Hematológicas/genética , Humanos , Janus Quinase 2/genética , Células K562 , Camundongos , Transtornos Mieloproliferativos/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
5.
Inflamm Bowel Dis ; 23(12): 2109-2120, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28930861

RESUMO

BACKGROUND: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. METHODS: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. RESULTS: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. CONCLUSIONS: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.


Assuntos
Diarreia/etiologia , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Idade de Início , Criança , Pré-Escolar , Doença Crônica , Feminino , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Sequenciamento Completo do Exoma
7.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
9.
BMC Bioinformatics ; 17: 151, 2016 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-27038897

RESUMO

BACKGROUND: Next generation sequencing (NGS) of amplified DNA is a powerful tool to describe genetic heterogeneity within cell populations that can both be used to investigate the clonal structure of cell populations and to perform genetic lineage tracing. For applications in which both abundant and rare sequences are biologically relevant, the relatively high error rate of NGS techniques complicates data analysis, as it is difficult to distinguish rare true sequences from spurious sequences that are generated by PCR or sequencing errors. This issue, for instance, applies to cellular barcoding strategies that aim to follow the amount and type of offspring of single cells, by supplying these with unique heritable DNA tags. RESULTS: Here, we use genetic barcoding data from the Illumina HiSeq platform to show that straightforward read threshold-based filtering of data is typically insufficient to filter out spurious barcodes. Importantly, we demonstrate that specific sequencing errors occur at an approximately constant rate across different samples that are sequenced in parallel. We exploit this observation by developing a novel approach to filter out spurious sequences. CONCLUSIONS: Application of our new method demonstrates its value in the identification of true sequences amongst spurious sequences in biological data sets.


Assuntos
Código de Barras de DNA Taxonômico , DNA/análise , Sequenciamento de Nucleotídeos em Larga Escala , Animais , Sequência de Bases , DNA/química , Camundongos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Células-Tronco/citologia , Células-Tronco/metabolismo
10.
Blood ; 128(2): 227-38, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27099149

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transativadores/imunologia
11.
Clin Immunol ; 164: 52-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26812624

RESUMO

NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet's disease. Hematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells - in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet's disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Quinase I-kappa B , Doenças Inflamatórias Intestinais/imunologia , Alelos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Feminino , Humanos , Quinase I-kappa B/deficiência , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Masculino , Irmãos
12.
Blood ; 126(14): 1658-69, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26289640

RESUMO

Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopenia with homeostatic proliferation, and lack of regulatory T cells are considered key factors in OS pathogenesis. We report 2 siblings presenting with cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150*), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Guanilato Ciclase/genética , Ativação Linfocitária/genética , Mutação , Imunodeficiência Combinada Severa/genética , Linfócitos T Reguladores/imunologia , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/imunologia , Feminino , Citometria de Fluxo , Guanilato Ciclase/deficiência , Guanilato Ciclase/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Imunofenotipagem , Lactente , Ativação Linfocitária/imunologia , Masculino , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Imunodeficiência Combinada Severa/imunologia , Irmãos
13.
Trends Immunol ; 36(7): 392-400, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26072285

RESUMO

Upon infection, antigen-specific T lymphocytes become activated, proliferate, differentiate, and acquire various effector functions. Much of our understanding of the molecular mechanisms underlying these processes derives from studies leveraging gene deletion, RNAi, and overexpression approaches. However, these perturbations do not inform on the regulation of gene activity under physiological conditions. Genetic reporter systems that couple biological events to detectable output signals are capable of providing this information. Here, we review the reporter approaches being currently used to investigate various aspects of T cell behavior, and discuss advantages and disadvantages inherent to different designs. We outline emerging applications based on recent advances in other fields, and highlight the potential of synthetic biology and genome engineering to address open questions in the field.


Assuntos
Diferenciação Celular/genética , Genes Reporter/genética , Engenharia Genética , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Humanos , Linfócitos T/metabolismo
14.
Trends Immunol ; 35(4): 170-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24657362

RESUMO

Upon primary infection, naïve T cells that recognize their cognate antigen become activated, proliferate, and simultaneously differentiate into various subsets. A long-standing question in the field has been how this cellular diversification is achieved. Conceptually, diverse cellular output may either arise from every single cell or only from populations of naïve cells. Furthermore, such diversity may either be driven by cell-intrinsic heterogeneity or by external, niche-derived signals. In this review, we discuss how recently developed technologies have allowed the analysis of the mechanisms underlying T cell diversification at the single cell level. In addition, we outline the implications of this work on our understanding of the formation of immunological memory, and describe a number of unresolved key questions in this field.


Assuntos
Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Humanos
15.
Science ; 340(6132): 635-9, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23493421

RESUMO

Upon infection, antigen-specific CD8(+) T lymphocyte responses display a highly reproducible pattern of expansion and contraction that is thought to reflect a uniform behavior of individual cells. We tracked the progeny of individual mouse CD8(+) T cells by in vivo lineage tracing and demonstrated that, even for T cells bearing identical T cell receptors, both clonal expansion and differentiation patterns are heterogeneous. As a consequence, individual naïve T lymphocytes contributed differentially to short- and long-term protection, as revealed by participation of their progeny during primary versus recall infections. The discordance in fate of individual naïve T cells argues against asymmetric division as a singular driver of CD8(+) T cell heterogeneity and demonstrates that reproducibility of CD8(+) T cell responses is achieved through population averaging.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Imunidade Celular , Memória Imunológica , Listeriose/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Divisão Celular Assimétrica , Linhagem da Célula , Proliferação de Células , Imunofenotipagem , Listeria monocytogenes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Processos Estocásticos , Subpopulações de Linfócitos T/citologia
16.
Haematologica ; 95(12): 2080-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20823128

RESUMO

BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed. DESIGN AND METHODS: We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2. RESULTS: All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal. CONCLUSIONS: Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.


Assuntos
Síndromes de Imunodeficiência/complicações , Linfo-Histiocitose Hemofagocítica/genética , Proteínas de Membrana/genética , Proteínas Munc18/genética , Mutação , Adolescente , Adulto , Alelos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Degranulação Celular/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Criança , Pré-Escolar , Citotoxicidade Imunológica/imunologia , Citometria de Fluxo , Frequência do Gene , Humanos , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/imunologia , Células K562 , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/imunologia , Sítios de Splice de RNA/genética
17.
Hum Mutat ; 31(2): 197-207, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19953608

RESUMO

The nuclease ARTEMIS is an essential factor of V(D)J recombination during lymphocyte development and in the repair of DNA double-strand breaks (DSB) by the nonhomologous end joining (NHEJ) pathway. Patients with mutations in the DCLRE1C gene, which encodes ARTEMIS, suffer from radiosensitive B(-/low) T(-/low) severe combined immunodeficiency (SCID) or radiosensitive Omenn syndrome. To date, causative DCLRE1C mutations inherited as a recessive trait have been reported in 49 patients. In this study, molecular diagnoses of 29 novel patients presenting with the phenotype of B(-/low) SCID revealed mutations in the DCLRE1C gene. In total, 13 different mutated DCLRE1C alleles were detected, nine of which have not been described before. By far the most frequent mutations (59%) were gross deletions of exons 1-3 or exons 1-4 due to a homologous recombination of the wild-type DCLRE1C gene with a pseudo-DCLRE1C gene located 61.2 kb 5' to the DCLRE1C start codon. Fine mapping of the recombination intervals revealed private mutations in most cases. MEIG1, a gene encoding a protein that is essential for spermatogenesis in mice, is lost by the gross deletions. Functional analyses on patients' fibroblasts demonstrated that the corresponding alleles carry null mutations of the DCLRE1C gene.


Assuntos
Mutação/genética , Proteínas Nucleares/genética , Recombinação Genética/genética , Linfócitos B/patologia , Bioensaio , Células Cultivadas , Proteínas de Ligação a DNA , Endonucleases , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Proteínas Nucleares/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tolerância a Radiação/genética , Deleção de Sequência/genética , Imunodeficiência Combinada Severa/genética , Éxons VDJ/genética
18.
J Clin Immunol ; 30(2): 314-20, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19967552

RESUMO

INTRODUCTION: We describe a girl presenting at age 6 years with a history of chronic ulcerating intestinal inflammation since 9 months of age. She exhibited a severe, steroid-dependent clinical course of intestinal inflammation over several years in the absence of serious infections. RESULTS AND DISCUSSION: Immunodeficiency was first considered at 6 years of age due to chronic lymphopenia. Immunophenotyping revealed low B and T cell counts with few naïve T cells, a skewed TCR repertoire, and TCR gamma/delta T cell predominance, suggesting a defect of lymphocyte development. Genetic and functional analyses identified a hypomorphic mutation in the DCLRE1C (ARTEMIS) gene compromising V(D)J recombination efficiency, but allowing residual T and B cell development. Hematopoetic stem cell transplantation reconstituted the lymphocyte compartment and cured the inflammatory bowel disease. CONCLUSION: This report illustrates that a genetic disorder of lymphocyte development can present with chronic inflammatory bowel disease as the dominant phenotype in the absence of severe infection susceptibility.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Proteínas Nucleares/genética , Linhagem Celular , Criança , Clonagem Molecular , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Diagnóstico Diferencial , Intervalo Livre de Doença , Endonucleases , Feminino , Genes Codificadores dos Receptores de Linfócitos T/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/fisiopatologia , Síndromes de Imunodeficiência/terapia , Imunofenotipagem , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/fisiopatologia , Doenças Inflamatórias Intestinais/terapia , Linfopenia , Linfopoese/genética , Mutação/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Transfecção , Úlcera
19.
Am J Hum Genet ; 85(4): 482-92, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19804848

RESUMO

Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Proteínas Munc18/genética , Proteínas Qa-SNARE/genética , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Exocitose , Feminino , Genótipo , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Proteínas Munc18/metabolismo , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Qa-SNARE/metabolismo , Proteínas SNARE/metabolismo
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