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1.
Clin Immunol ; 200: 31-34, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639166

RESUMO

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.


Assuntos
Agamaglobulinemia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Linfopenia/genética , Doenças da Imunodeficiência Primária/genética , Adulto , Agamaglobulinemia/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Mutação com Ganho de Função , Humanos , Linfopenia/imunologia , Linfopoese , Doenças da Imunodeficiência Primária/imunologia
2.
Clin Immunol ; 175: 99-108, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27923702

RESUMO

NFKB1, a component of the canonical NF-κB pathway, was recently reported to be mutated in a limited number of CVID patients. CVID-associated mutations in NFKB2 (non-canonical pathway) have previously been shown to impair NK cell cytotoxic activity. Although a biological function of NFKB1 in non-human NK cells has been reported, the role of NFKB1 mutations for human NK cell biology and disease has not been investigated yet. We decided therefore to evaluate the role of monoallelic NFKB1 mutations in human NK cell maturation and functions. We show that NFKB1 mutated NK cells present impaired maturation, defective cytotoxicity and reduced IFN-γ production upon in vitro stimulation. Furthermore, human IL-2 activated NFKB1 mutated NK cells fail to up-regulate the expression of the activating marker NKp44 and show reduced proliferative capacity. These data suggest that NFKB1 plays an essential novel role for human NK cell maturation and effector functions.


Assuntos
Células Matadoras Naturais/imunologia , Subunidade p50 de NF-kappa B/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-2/imunologia , Células K562 , Masculino , NF-kappa B/imunologia
3.
J Immunol ; 195(1): 246-56, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26026062

RESUMO

Previous work has shown conflicting roles for Tec family kinases in regulation of TLR-dependent signaling in myeloid cells. In the present study, we performed a detailed investigation of the role of the Tec kinases Btk and Tec kinases in regulating TLR signaling in several types of primary murine macrophages. We demonstrate that primary resident peritoneal macrophages deficient for Btk and Tec secrete less proinflammatory cytokines in response to TLR stimulation than do wild-type cells. In contrast, we found that bone marrow-derived and thioglycollate-elicited peritoneal macrophages deficient for Btk and Tec secrete more proinflammatory cytokines than do wild-type cells. We then compared the phosphoproteome regulated by Tec kinases and LPS in primary peritoneal and bone marrow-derived macrophages. From this analysis we determined that Tec kinases regulate different signaling programs in these cell types. In additional studies using bone marrow-derived macrophages, we found that Tec and Btk promote phosphorylation events necessary for immunoreceptor-mediated inhibition of TLR signaling. Taken together, our results are consistent with a model where Tec kinases (Btk, Tec, Bmx) are required for TLR-dependent signaling in many types of myeloid cells. However, our data also support a cell type-specific TLR inhibitory role for Btk and Tec that is mediated by immunoreceptor activation and signaling via PI3K.


Assuntos
Macrófagos/imunologia , Fosfoproteínas/imunologia , Proteínas Tirosina Quinases/imunologia , Tirosina Quinase da Agamaglobulinemia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos , Cavidade Peritoneal/citologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Fosfoproteínas/genética , Fosforilação , Cultura Primária de Células , Proteínas Tirosina Quinases/genética , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
4.
Clin Immunol ; 163: 10-3, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26686461

RESUMO

B cell developmental defects in CVID were recently described in a limited number of cases. To date, a detailed correlation between this maturational defect and the clinical presentation of affected patients has not been reported. In this study, we correlated bone marrow B cell evaluation, peripheral B and T lymphocyte subsets and clinical findings in 15 CVID patients. Early B cell developmental defects were observed in one third of patients. Combined bone marrow and peripheral lymphocytes evaluation allowed to further subdivide CVID patients in three groups with shared clinical features at diagnosis and during follow-up. These data broaden the number of CVID patients with early B cell developmental defects and, together with the peripheral lymphocytes evaluation, offer insight into the related clinical features in affected patients.


Assuntos
Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Imunodeficiência de Variável Comum/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Subpopulações de Linfócitos B/imunologia , Medula Óssea , Bronquiectasia/etiologia , Bronquiectasia/imunologia , Imunodeficiência de Variável Comum/complicações , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/etiologia , Infecções Respiratórias/imunologia , Esplenomegalia/etiologia , Esplenomegalia/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
5.
Am J Hum Genet ; 90(6): 986-1001, 2012 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-22608502

RESUMO

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Autoimunidade/genética , Síndromes de Imunodeficiência/genética , Agamaglobulinemia/genética , Apoptose , Autofagia , Linfócitos B/citologia , Proliferação de Células , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Ligação Genética , Genótipo , Homozigoto , Humanos , Imunofenotipagem , Masculino , Microscopia Eletrônica de Transmissão/métodos , Modelos Genéticos , Mutação , Linhagem , Fenótipo
6.
J Allergy Clin Immunol ; 133(6): 1644-50.e4, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24612681

RESUMO

BACKGROUND: Bruton tyrosine kinase (BTK) plays an essential role in various biologic functions of different cell types. Mutations in BTK lead to X-linked agammaglobulinemia (XLA) in humans. BTK was recently linked to the innate immune system, in particular, the Toll-like receptor (TLR) pathway; however, the TLR9 pathway has never been studied in dendritic cells (DCs) of patients with XLA. OBJECTIVE: The aim of this study was to investigate the role of BTK in human DC activation upon TLR9 stimulation. METHODS: DCs of patients with XLA and healthy donors were stimulated via TLR4/9 and evaluated for cell activation and cytokine production. RESULTS: We showed that BTK plays an essential role in DC responses to unmethylated CpG oligodeoxynucleotide: although responses to lipopolysaccaride/TLR4 induce normal DC activation in terms of upregulation of specific markers (CD86, CD83, CD80, HLA-DR), the CpG/TLR9 pathway is completely impaired in patients with XLA. Furthermore, cytokine production upon TLR9 activation in patients with XLA is radically impaired in terms of IL-6, IL-12, TNF-α, and IL-10 production. Interestingly, BTK mediated STAT1/3 upregulation in a TLR9-dependent manner. The important role of BTK in human DC activation was confirmed after incubation of healthy DCs with ibrutinib, the specific BTK inhibitor, which resulted in impairment of TLR9 responses as seen in patients with XLA. CONCLUSION: Analysis of these data suggests that BTK regulates human DC responses upon TLR9 engagement in terms of activation, cytokine production, and STAT1/3 upregulation. These findings may be of important significance for better understanding and managing different clinical conditions, such as agammaglobulinemia and lymphoid malignancies.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptor Toll-Like 9/metabolismo , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/metabolismo , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Imunofenotipagem , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Oligodesoxirribonucleotídeos/farmacologia , Fenótipo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo
8.
J Clin Invest ; 134(9)2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38502193

RESUMO

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.


Assuntos
Leucemia Mieloide Aguda , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Sirolimo , Linfócitos T , Animais , Feminino , Humanos , Masculino , Camundongos , Imunoterapia Adotiva , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Receptores de Antígenos Quiméricos/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Sirolimo/farmacologia , Sirolimo/administração & dosagem , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
ScientificWorldJournal ; 2012: 960219, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22454615

RESUMO

Broad Toll-like receptor 9 (TLR9) signalling defects after CpG in vitro stimulation have been described in common variable immunodeficiency (CVID). CXCL16, a surface receptor, was recently shown to influence cell responses to CpG. We evaluated the expression and function of CXCL16 on B cells from healthy controls and CVID patients. We report that CXCL16 is normally expressed on B cells throughout peripheral maturation. Decreased B cell expression of CXCL16 was observed in a subgroup of CVID patients that correlated with defective in vitro responses to CpG (such as upregulation of CD69, CD86, AICDA, IL-6, and TLR9). Our data suggest that expression levels of a surface receptor, namely, CXCL16, correlate with B cell responses mediated by TLR9 in common variable immunodeficiency.


Assuntos
Linfócitos B/imunologia , Quimiocinas CXC/genética , Imunodeficiência de Variável Comum/imunologia , Ilhas de CpG/imunologia , Receptores Depuradores/genética , Adolescente , Adulto , Estudos de Casos e Controles , Quimiocina CXCL16 , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
12.
J Immunol ; 183(12): 8280-5, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20007591

RESUMO

Selective IgA deficiency (IGAD) is the most common primary immunodeficiency, yet its pathogenesis is elusive. The IG (heavy) H chain human 3' Regulatory Region harbors three enhancers and has an important role in Ig synthesis. HS1.2 is the only polymorphic enhancer of the 3' RRs. We therefore evaluated HS1.2 allelic frequencies in 88 IGAD patients and 101 controls. Our data show that IGAD patients have a highly significant increase of homozygousity of the allele *1 (39% in the IGAD patients and 15% in controls), with an increase of 2.6-fold. Allele *4 has a similar trend of allele *2, both showing a significant decrease of frequency in IGAD. No relationship was observed between allele *1 frequencies and serum levels of IgG. However, allele *1 was associated in IGAD patients with relatively low IgM levels (within the 30th lowest percentile of patients). The HS1.2 polymorphism influences Ig seric production, but not IgG switch, in fact 30th lowest or highest percentile of IgG in patients did not associate to different frequencies of HS1.2 alleles. The control on normal healthy subjects did not correlate high or low levels of IgM or IgG with HS1.2 allelic frequence variation. Overall our candidate gene approach confirms that the study of polymorphisms in human diseases is a valid tool to investigate the function of these Regulatory Regions that confers multiple immune features.


Assuntos
Alelos , Elementos Facilitadores Genéticos/imunologia , Deficiência de IgA/genética , Deficiência de IgA/imunologia , Imunoglobulina M/sangue , Região 3'-Flanqueadora/imunologia , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Feminino , Frequência do Gene/imunologia , Humanos , Deficiência de IgA/sangue , Imunoglobulina G/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulina M/genética , Região de Troca de Imunoglobulinas/genética , Masculino , Dados de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico/imunologia , Adulto Jovem
13.
J Allergy Clin Immunol ; 135(6): 1641-3, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25605273
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