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1.
Nat Immunol ; 17(11): 1291-1299, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27618553

RESUMO

Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.


Assuntos
Imunidade Inata , Linfócitos/imunologia , Adolescente , Adulto , Animais , Biomarcadores , Criança , Modelos Animais de Doenças , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Subunidade gama Comum de Receptores de Interleucina/deficiência , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Janus Quinase 3/deficiência , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Linfopenia/sangue , Linfopenia/etiologia , Camundongos , Camundongos Knockout , Fenótipo , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/terapia , Pele/imunologia , Pele/patologia
2.
Immunity ; 49(5): 971-986.e5, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30413361

RESUMO

Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.


Assuntos
Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/metabolismo , Transcriptoma , Animais , Biomarcadores , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade Inata , Imunofenotipagem , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Camundongos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Fenótipo , Análise de Célula Única
3.
Nature ; 588(7836): 146-150, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32726800

RESUMO

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Complemento C5a/imunologia , Inflamação/complicações , Inflamação/imunologia , Receptor da Anafilatoxina C5a/imunologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , COVID-19/sangue , COVID-19/patologia , Complemento C5a/antagonistas & inibidores , Complemento C5a/biossíntese , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/sangue , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
5.
Crit Care Med ; 50(12): 1788-1798, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36218354

RESUMO

OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Anticorpos Monoclonais Humanizados/uso terapêutico , Oxigênio , Resultado do Tratamento
6.
Blood ; 136(5): 542-552, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32356861

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition. Primary HLH occurs early in life as a result of monogenic biallelic mutations affecting lymphocyte cytotoxicity. Secondary HLH occurs mostly in adults secondary to infection, lymphoma, or rheumatic disease. In this latter setting, lymphocyte cytotoxicity status is not known. We conducted a systematic evaluation of natural killer (NK) cell cytotoxicity in adult patients with secondary HLH. Adult patients with secondary HLH were prospectively studied ex vivo for total lymphocyte count and subtype, NK cell phenotype, perforin expression and degranulation, and natural or antibody-dependent cell cytotoxicity, in comparison with patients affected by the same underlying disease without HLH (disease controls [DCs]) and with healthy controls (HCs). Screening for variants of cytotoxity genes was systematically performed. 68 patients were included in the HLH group and 34 each in the DC and HC groups. In HLH patients, severe and transient lymphopenia, activated NK cell phenotype (eg, increased CD69, ICAM-1, HLADR, and CCR5 expression), and decreased capacity of interferon γ production were observed; mean perforin expression was normal; and degranulation tests and NK cell cytotoxicity were not different from those in DCs. A monoallelic variant of uncertain significance affecting a lymphocyte cytotoxicity gene or the perforin variant A91V was observed in almost 50% of the patients. We detected no major intrinsic cytotoxicity dysfunction in secondary HLH patients compared with DCs and no predicted pathogenic gene variant. The activated NK phenotype profile associated with decreased interferon γ production seems similar to those of other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.


Assuntos
Inflamação/imunologia , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Testes Imunológicos de Citotoxicidade , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Feminino , Testes Genéticos , Humanos , Inflamação/genética , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Pessoa de Meia-Idade
8.
J Neurochem ; 134(3): 527-37, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25950943

RESUMO

The axon initial segment (AIS) plays a central role in electrogenesis and in the maintenance of neuronal polarity. Its molecular organization is dependent on the scaffolding protein ankyrin (Ank) G and is regulated by kinases. For example, the phosphorylation of voltage-gated sodium channels by the protein kinase CK2 regulates their interaction with AnkG and, consequently, their accumulation at the AIS. We previously showed that IQ motif containing J-Schwannomin-Interacting Protein 1 (IQCJ-SCHIP-1), an isoform of the SCHIP-1, accumulated at the AIS in vivo. Here, we analyzed the molecular mechanisms involved in IQCJ-SCHIP-1-specific axonal location. We showed that IQCJ-SCHIP-1 accumulation in the AIS of cultured hippocampal neurons depended on AnkG expression. Pull-down assays and surface plasmon resonance analysis demonstrated that AnkG binds to CK2-phosphorylated IQCJ-SCHIP-1 but not to the non-phosphorylated protein. Surface plasmon resonance approaches using IQCJ-SCHIP-1, SCHIP-1a, another SCHIP-1 isoform, and their C-terminus tail mutants revealed that a segment including multiple CK2-phosphorylatable sites was directly involved in the interaction with AnkG. Pharmacological inhibition of CK2 diminished both IQCJ-SCHIP-1 and AnkG accumulation in the AIS. Silencing SCHIP-1 expression reduced AnkG cluster at the AIS. Finally, over-expression of IQCJ-SCHIP-1 decreased AnkG concentration at the AIS, whereas a mutant deleted of the CK2-regulated AnkG interaction site did not. Our study reveals that CK2-regulated IQJC-SCHIP-1 association with AnkG contributes to AIS maintenance. The axon initial segment (AIS) organization depends on ankyrin (Ank) G and kinases. Here we showed that AnkG binds to CK2-phosphorylated IQCJ-SCHIP-1, in a segment including 12 CK2-phosphorylatable sites. In cultured neurons, either pharmacological inhibition of CK2 or IQCJ-SCHIP-1 silencing reduced AnkG clustering. Overexpressed IQCJ-SCHIP-1 decreased AnkG concentration at the AIS whereas a mutant deleted of the CK2-regulated AnkG interaction site did not. Thus, CK2-regulated IQJC-SCHIP-1 association with AnkG contributes to AIS maintenance.


Assuntos
Anquirinas/metabolismo , Axônios/metabolismo , Proteínas de Transporte/metabolismo , Caseína Quinase II/metabolismo , Animais , Western Blotting , Células Cultivadas , Imunofluorescência , Hipocampo/metabolismo , Camundongos , Microscopia Confocal , Dados de Sequência Molecular , Ratos , Ratos Wistar , Ressonância de Plasmônio de Superfície , Transfecção
9.
Blood ; 122(3): 394-404, 2013 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-23687088

RESUMO

B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14(+)CD16(+) proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1ß and tumor necrosis factor α. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14(+)CD16(+) monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions.


Assuntos
Antígenos B7/metabolismo , Inflamação/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Anticorpos Monoclonais/metabolismo , Antígenos B7/sangue , Antígenos B7/genética , Antígenos B7/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Humanos , Inflamação/patologia , Ligantes , Monócitos/metabolismo , Neutrófilos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/imunologia , Sepse/patologia , Solubilidade
10.
Ann Endocrinol (Paris) ; 85(3): 226-230, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38871498

RESUMO

IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.


Assuntos
Imunidade Adaptativa , Tecido Adiposo , Imunidade Inata , Pericárdio , Humanos , Pericárdio/imunologia , Pericárdio/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Tecido Adiposo/imunologia , Idoso , Adulto , Linfócitos/imunologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Transcriptoma , Tecido Adiposo Epicárdico
11.
Obesity (Silver Spring) ; 32(7): 1302-1314, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38747118

RESUMO

OBJECTIVE: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features. METHODS: First, a new pan-genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study). RESULTS: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4+T cells, CD8+T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL-13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT-ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL-33 and uncoupling protein 1 [UCP-1]) in EAT. CONCLUSIONS: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging.


Assuntos
Imunidade Inata , Linfócitos , Pericárdio , Gordura Subcutânea , Humanos , Pericárdio/metabolismo , Masculino , Gordura Subcutânea/metabolismo , Gordura Subcutânea/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Feminino , Pessoa de Meia-Idade , Tecido Adiposo Bege/metabolismo , Adulto , Idoso , Imunofenotipagem , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Th2/imunologia , Tecido Adiposo Epicárdico
12.
J Leukoc Biol ; 111(1): 161-172, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33847423

RESUMO

Lymphocytes are essential for microbial immunity, tumor surveillance, and tissue homeostasis. However, the in vivo development and function of helper-like innate lymphoid cells (ILCs) in humans remain much less well understood than those of T, B, and NK cells. We monitored hematopoietic stem cell transplantation (HSCT) to determine the kinetics of ILC development in both children and adults. It was found that, unlike NK cells, helper-like ILCs recovered slowly, mirroring the pattern observed for T cells, with normalization achieved at 1 year. The type of graft and the proportion of CD34+ cells in the graft did not significantly affect ILC reconstitution. As HSCT is often complicated by acute or chronic graft-versus-host disease (GVHD), the potential role of ILC subsets in maintaining tissue integrity in these conditions was also analyzed. It was found that GVHD was associated with lower levels of activated and gut-homing NKp44+ ILCP, consistent with a non-redundant role of this ILC subset in preventing this life-threatening disorder in lymphopenic conditions.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunidade Inata , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
13.
Cell Mol Immunol ; 18(5): 1290-1304, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33239726

RESUMO

Natural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56bright NK cells, NK0 cells, as the precursor of both circulating CD56dim NK1-like NK cells and CD56bright NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160high group had a significantly higher survival rate.


Assuntos
Células da Medula Óssea/patologia , Diferenciação Celular , Células Matadoras Naturais/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Análise de Célula Única , Estresse Fisiológico , Antígenos CD/metabolismo , Regulação Leucêmica da Expressão Gênica , Ontologia Genética , Humanos , RNA-Seq , Doadores de Tecidos , Transcriptoma/genética
14.
Front Immunol ; 10: 2179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616411

RESUMO

Background: Septic shock, a major cause of death in critical care, is the clinical translation of a cytokine storm in response to infection. It can be complicated by sepsis-induced immunosuppression, exemplified by blood lymphopenia, an excess of circulating Treg lymphocytes, and decreased HLA-DR expression on circulating monocytes. Such immunosuppression is associated with secondary infections, and higher mortality. The effect of these biological modifications on circulating innate lymphoid cells (ILCs) has been little studied. Methods: We prospectively enrolled patients with septic shock (Sepsis-3 definition) in the intensive care unit (ICU) of Timone CHU Hospital. ICU controls (trauma, cardiac arrest, neurological dysfunction) were recruited at the same time (NCT03297203). We performed immunophenotyping of adaptive lymphocytes (CD3+ T cells, CD19+ B cells, CD4+CD25+FoxP3+ Treg lymphocytes), ILCs (CD3-CD56+ NK cells and helper ILCs - ILC1, ILC2, and ILC3), and monocytes by flow cytometry on fresh blood samples collected between 24 and 72 h after admission. Results: We investigated adaptive and innate circulating lymphoid cells in the peripheral blood of 18 patients in septic shock, 15 ICU controls, and 30 healthy subjects. As expected, the peripheral blood lymphocytes of all ICU patients showed lymphopenia, which was not specific to sepsis, whereas those of the healthy volunteers did not. Circulating CD3+ T cells and CD3-CD56+ NK cells were mainly concerned. There was a tendency toward fewer Treg lymphocytes and lower HLA-DR expression on monocytes in ICU patients with sepsis. Although the ILC1 count was higher in septic patients than healthy subjects, ILC2, and ILC3 counts were lower in both ICU groups. However, ILC3s within the total ILCs were overrepresented in patients with septic shock. The depression of immune responses has been correlated with the occurrence of secondary infections. We did not find any differences in ILC distribution according to this criterion. Conclusion: All ICU patients exhibit lymphopenia, regardless of the nature (septic or sterile) of the initial medical condition. Specific distribution of circulating ILCs, with an excess of ILC1, and a lack of ILC3, may characterize septic shock during the first 3 days of the disease.


Assuntos
Linfócitos/imunologia , Choque Séptico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Front Immunol ; 8: 235, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28348556

RESUMO

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of TH1/TH2/TH17, TFH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, TH2, TH17, and CD4+CXCR5+PD1+ TFH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. TFH increase was characterized by the specific expansion of TFH2 (CCR6-CXCR3-), and to a lesser extent of TFH17 (CCR6+CXCR3-) cells. Interestingly, CD4+CXCR5+PD1+ TFH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a TH2/TFH2 and TH17/TFH17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.

16.
Oncoimmunology ; 6(1): e1137418, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28197361

RESUMO

Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

17.
J Clin Invest ; 127(5): 1991-2006, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414293

RESUMO

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.


Assuntos
Proteínas de Ligação a DNA/deficiência , Doenças Genéticas Inatas , Transtornos do Crescimento , Síndromes de Imunodeficiência , Células Matadoras Naturais , Neutropenia , Animais , Proteínas de Ligação a DNA/imunologia , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Camundongos , Neutropenia/genética , Neutropenia/imunologia
19.
Cancer Immunol Res ; 3(10): 1109-14, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26438443

RESUMO

The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNγ. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples.


Assuntos
Imunidade Inata , Subpopulações de Linfócitos/imunologia , Neoplasias/imunologia , Animais , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Fenótipo
20.
Sci Transl Med ; 7(283): 283ra55, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25877893

RESUMO

The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P < 0.001), adding prognostic value to known risk factors such as N-Myc amplification and age >18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.


Assuntos
Antígenos B7/metabolismo , Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Neuroblastoma/metabolismo , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Criança , Pré-Escolar , Intervalo Livre de Doença , Humanos , Lactente , Células Jurkat , Ligantes , Metástase Neoplásica , Neuroblastoma/mortalidade , Fenótipo , Prognóstico , Estudos Prospectivos , Ligação Proteica , Fatores de Risco , Adulto Jovem
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