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1.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

2.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
3.
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
4.
J Immunol ; 194(7): 3045-53, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25732729

RESUMO

The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αß T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his "untouched" naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αß T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good's syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αß T cells and an increased susceptibility to infections.


Assuntos
Complexo CD3/genética , Regulação da Expressão Gênica , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timoma/genética , Timoma/imunologia , Adulto , Antígenos de Protozoários/imunologia , Complexo CD3/metabolismo , Citocinas/biossíntese , Éxons , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Memória Imunológica , Imunofenotipagem , Leishmania/imunologia , Contagem de Linfócitos , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Análise de Sequência de DNA , Timoma/complicações , Timoma/diagnóstico
5.
Eur J Immunol ; 44(10): 3129-40, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042067

RESUMO

X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4

Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células Matadoras Naturais/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Mutação , Fenótipo , Transdução de Sinais/imunologia
6.
Haematologica ; 98(12): 1948-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23850805

RESUMO

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/ß(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.


Assuntos
Proteína Ligante Fas/sangue , Proteína Ligante Fas/genética , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/genética , Vitamina B 12/sangue , Adolescente , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Transtornos Linfoproliferativos/diagnóstico , Masculino
7.
J Cell Commun Signal ; 5(2): 145-56, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21484192

RESUMO

Severe trauma and the systemic inflammatory response syndrome (SIRS) occur as a result of a cytokine storm which is in part due to ATP released from damaged tissue. This pathology also leads to increased numbers of immature antigen presenting cells (APC) sharing properties of dendritic cells (DC) or macrophages (MΦ). The occurrence of immature APC appears to coincide with the reactivation of herpes virus infections such as Epstein Barr virus (EBV). The aim of this study was the comparative analysis of the ultrastructural and functional characteristics of such immature APC. In addition, we investigated EBV infection/ reactivation and whether immature APC might be targets for natural killers (NK). Significant macroautophagy, mitochondrial degradation and multivesicular body formation together with the identification of herpes virus particles were morphological findings associated with immature APC. Exogenous stressors such as ATP further increased morphological signs of autophagy, including LC3 expression. Functional tests using fluorescent bacteria proved impaired phagolysosome fusion. However, immature APC were susceptible to NK-92-mediated cytolysis. We found evidence for EBV latency state II infection by detecting EBV-specific LMP1 and EBNA2 in immature APC and in whole blood of these patients. In summary, trauma-induced cytokine storms may induce maturation arrest of APC, promote ATP-induced autophagy, support EBV persistence and impair the degradation of phagocytozed bacteria through inefficient phagolysosome fusion. The susceptibility to NK-mediated cytolysis supports the hypothesis that NK function is likely to contribute to immune reconstitution after major trauma by regulating immature APC, and ATP-induced autophagy and survival.

8.
Macromol Biosci ; 8(8): 711-27, 2008 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-18504805

RESUMO

Fluorescent polyisoprene nanoparticles were synthesized by the miniemulsion technique as marker particles for cells. The uptake of the non-functionalized polyisoprene nanoparticles, without any transfection agents, into different adherent (HeLa) and also suspension (Jurkat) cell lines is strikingly efficient and fast compared to other polymeric particles, and leads to high loading of the cells. The intracellular polyisoprene particles are localized as single particles in endosomes distributed throughout the entire cytoplasm. The uptake kinetics shows that particle internalization starts during the first minutes of incubation and is finished after 48 h of incubation. Since (unfunctionalized) polystyrene particles show a comparable, low uptake behavior in cells, the uptake rates can be tuned by the amount of polystyrene in polyisoprene/polystyrene copolymer particles. As polyisoprene nanoparticles are internalized by different cell lines that are relevant for biomedical applications, they can be used to label these cells efficiently if a marker is incorporated in the particles. As polyisoprene is not or is hardly biodegradable the particles should be suited for long-term applications.


Assuntos
Butadienos/síntese química , Butadienos/farmacologia , Endossomos/ultraestrutura , Corantes Fluorescentes/síntese química , Hemiterpenos/síntese química , Hemiterpenos/farmacologia , Nanopartículas , Pentanos/síntese química , Pentanos/farmacologia , Poliestirenos/síntese química , Poliestirenos/farmacologia , Butadienos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Células HeLa , Hemiterpenos/química , Humanos , Células Jurkat , Cinética , Nanopartículas/química , Pentanos/química , Poliestirenos/química , Fatores de Tempo
9.
Macromol Biosci ; 7(7): 883-96, 2007 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-17595680

RESUMO

Fluorescent dye labeled unfunctionalized and functionalized poly(n-butylcyanoacrylate) nanoparticles were prepared using a miniemulsion technique. Amino acid and methoxyPEG functionalization could be introduced by using aqueous solutions as an initiator for the anionic polymerization in the heterophase. All the particles prepared had sizes smaller than 250 nm and negative zeta-potentials. The molar mass distribution of the polymer was dependent on the acid used as the continuous phase and the initiator solution applied. Cells of three lines (HeLa, Jurkat and mesenchymal stem cells) were incubated with the particles. The molar mass of the polymer determined the onset and extent of apoptosis, and the total uptake was determined by the size and functionalization of the particles. Different uptake kinetics were obtained with HeLa and Jurkat cells after incubation with the same particle batch. The intracellular particle distribution, visualized by confocal laser scanning microscopy, did not show significant differences for either of the cell lines or particle batches.


Assuntos
Células/metabolismo , Portadores de Fármacos/síntese química , Embucrilato/síntese química , Aminoácidos , Apoptose , Linhagem Celular , Portadores de Fármacos/farmacocinética , Emulsões/química , Embucrilato/farmacocinética , Corantes Fluorescentes , Células HeLa , Humanos , Células Jurkat , Cinética , Células-Tronco Mesenquimais , Nanopartículas/química , Tamanho da Partícula , Polietilenoglicóis
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