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1.
Clin Immunol ; 201: 30-34, 2019 Apr.
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.

2.
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
3.
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
4.
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
5.
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
6.
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
7.
Pediatr Transplant ; 12(4): 426-31, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18466428

RESUMO

The development of lymphomas after SOT is a well-known complication of the immunosuppressive therapy necessary to prevent graft rejection. Epstein-Barr virus plays a central role in the pathogenesis of lymphomas because of its ability to transform infected cells. Differentiating PTLD from malignant lymphomas, especially HL can be challenging. We report on two patients, who developed EBV-associated lymphomas several years after SOT. A histological examination of lymph nodes led to a diagnosis of HL in both patients, who were started on chemotherapy according to current treatment protocols. A rapid and complete remission in one patient prompted us to analyze the expression pattern of EBV-latency genes. In this patient, the EBV expression profile revealed a latency type III suggesting the diagnosis of Hodgkin-like PTLD. The other patient required six courses of chemotherapy plus radiotherapy to reach a complete remission. In his tumor cells, a restricted EBV-latency type II pattern was found, suggesting a diagnosis of classical HL. These two cases demonstrate that in post-transplant lymphomas with histological features of HL, an analysis of the expression pattern of EBV proteins might aid in the differentiation between PTLD and HL.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/metabolismo , Doença de Hodgkin/etiologia , Doença de Hodgkin/virologia , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/virologia , Adolescente , Antineoplásicos/uso terapêutico , Criança , Ciclosporina/efeitos adversos , Diagnóstico Diferencial , Humanos , Imunossupressores/efeitos adversos , Linfonodos/patologia , Masculino
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