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1.
J Exp Med ; 217(3)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31914175

RESUMO

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

3.
Nat Immunol ; 20(1): 109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448856

RESUMO

In the version of this article initially published, in the legend to Fig. 1b, the description of the frequency of TH17-IL-10+ clones was incomplete for the first group; this should read as follows: "...13 experiments with clones isolated from CCR6+CCR4+CXCR3- T cells...". Also, the label along the vertical axis of the bottom right plot in Figure 5b was incomplete; the correct label is 'IFN-γ+ cells (%)'. Finally, in the first sentence of the final paragraph of the final Results subsection, the description of the regions analyzed was incorrect; that sentence should begin: "DNA motif-enrichment analysis of the subset-specific H3K27ac-positive regions...". The errors have been corrected in the HTML and PDF versions of the article.

4.
Haematologica ; 104(3): 609-621, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30309848

RESUMO

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.

5.
Nat Immunol ; 19(10): 1126-1136, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201991

RESUMO

Different types of effector and memory T lymphocytes are induced and maintained in protective or pathological immune responses. Here we characterized two human CD4+ TH17 helper cell subsets that, in the recently activated state, could be distinguished on the basis of their expression of the anti-inflammatory cytokine IL-10. IL-10+ TH17 cells upregulated a variety of genes encoding immunoregulatory molecules, as well as genes whose expression is characteristic of tissue-resident T cells. In contrast, IL-10- TH17 cells maintained a pro-inflammatory gene-expression profile and upregulated the expression of homing receptors that guide recirculation from tissues to blood. Expression of the transcription factor c-MAF was selectively upregulated in IL-10+ TH17 cells, and it was bound to a large set of enhancer-like regions and modulated the immunoregulatory and tissue-residency program. Our results identify c-MAF as a relevant factor that drives two highly divergent post-activation fates of human TH17 cells and provide a framework with which to investigate the role of these cells in physiology and immunopathology.


Assuntos
Interleucina-10/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Quimiotaxia de Leucócito/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/imunologia , Interleucina-10/biossíntese , Proteínas Proto-Oncogênicas c-maf/metabolismo , Subpopulações de Linfócitos T/metabolismo , Células Th17/metabolismo
6.
Nat Commun ; 8(1): 1600, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29150604

RESUMO

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ-IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases.


Assuntos
Perfilação da Expressão Gênica , Interleucina-10/genética , Esclerose Múltipla/genética , Células Th17/metabolismo , Adulto , Animais , Células Cultivadas , Feminino , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Células Th1/metabolismo
7.
J Exp Med ; 214(9): 2547-2562, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28747427

RESUMO

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.


Assuntos
Craniossinostoses/genética , Receptor gp130 de Citocina/genética , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto/genética , Pré-Escolar , Receptor gp130 de Citocina/fisiologia , Exoma/genética , Feminino , Humanos , Interleucina-11/deficiência , Interleucina-6/deficiência , Interleucinas/deficiência
8.
Nat Commun ; 6: 6431, 2015 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-25775432

RESUMO

T helper (TH) cell polarization during priming is modulated by a number of signals, but whether polarization to a given phenotype also influences recall responses of memory TH cells is relatively unknown. Here we show that miR-181a is selectively induced in both human and mouse naive T cells differentiating into the TH17, but not TH1 or TH2 subset. In human memory TH17 cells, miR-181a regulates responses to cognate antigens through modulation of ERK phosphorylation. By enhancing the signalling cascade from the T-cell receptor, such molecular network reduces the threshold of TH17 cell activation. Moreover, at a late time point, the same network induces a self-regulatory mechanism dependent on ID3, a negative regulator of transcription factors that control RORC expression, thus modulating TH17 activity. Our results demonstrate that the phenotype acquired by TH cells during priming contributes to their threshold of activation to secondary antigenic stimulations, thus influencing memory responses.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Memória Imunológica , MicroRNAs/metabolismo , Células Th17/citologia , Animais , Antígenos/química , Candida albicans/metabolismo , Diferenciação Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Fenótipo , Fosforilação , Interferência de RNA , Transdução de Sinais
9.
Nature ; 484(7395): 514-8, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22466287

RESUMO

IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity. However, the requirements for differentiation and the properties of pathogen-induced human TH17 cells remain poorly defined. Using an approach that combines the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, we describe here two types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific TH17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1ß contributed to TH17 differentiation induced by both pathogens, but IL-1ß was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-γ double-producing cells. In addition, IL-1ß inhibited IL-10 production in differentiating and in memory TH17 cells, whereas blockade of IL-1ß in vivo led to increased IL-10 production by memory TH17 cells. We also show that, after restimulation, TH17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-γt. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime TH17 cells that produce either IFN-γ or IL-10, and identify IL-1ß and IL-2 as pro- and anti-inflammatory regulators of TH17 cells both at priming and in the effector phase.


Assuntos
Candida albicans/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-1beta/imunologia , Staphylococcus aureus/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Apresentação do Antígeno/imunologia , Diferenciação Celular , Regulação para Baixo , Humanos , Memória Imunológica/imunologia , Interleucina-17/biossíntese , Interleucina-2/antagonistas & inibidores , Interleucina-2/imunologia , Ativação Linfocitária , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT5/metabolismo , Células Th17/citologia , Fator de Necrose Tumoral alfa/metabolismo
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