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1.
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.

2.
PLoS One ; 13(11): e0206105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30395619

RESUMO

BACKGROUND: Fibroproliferative repair phase of the acute respiratory distress syndrome (ARDS) is followed by a restitutio ad integrum of lung parenchyma or by an irreversible lung fibrosis and patients' death. Transforming Growth Factor-ß1 (TGF-ß1) is involved in collagen production and lung repair. We investigated whether alveolar TGF-ß1 was associated with the presence of fibroproliferation and the outcome of ARDS patients. METHODS: Sixty-two patients were included the first day of moderate-to-severe ARDS. Bronchoalveolar lavage fluid (BALF) was collected at day 3 (and day 7 when the patients were still receiving invasive mechanical ventilation) from the onset of ARDS. Survival was evaluated at day 60. TGF-ß1 was measured by immunoassay. The patients were classified as having lung fibroproliferation when the alveolar N-terminal peptide for type III procollagen (NT-PCP-III) measured on day 3 was > 9 µg/L as recently reported. The main objective of this study was to compare the alveolar levels of total TGF-ß1 according to the presence or not a lung fibroproliferation at day 3. RESULTS: Forty-three patients (30.6%) presented a fibroproliferation at day 3. BALF levels of total TGF-ß1 were not statistically different at day 3 (and at day 7) according to the presence or not lung fibroproliferation. Mortality at day 60 was higher in the group of patients with fibroproliferation as compared with patients with no fibroproliferation (68.4% vs. 18.6% respectively; p < 0.001). Total TGF-ß1 measured on BALF at day 3 was not associated with the outcome. Multiple logistic regression showed that the presence of lung fibroproliferation was associated with death. In contrast, TGF-ß1 was not independently associated with death. CONCLUSIONS: Pulmonary levels of TGF-ß1 during the first week of ARDS were not associated nor with the presence of fibroproliferation neither with death. TGF-ß1 should not be used as a biomarker to direct anti-fibrotic therapies.

3.
J Clin Invest ; 128(7): 3071-3087, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889099

RESUMO

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

4.
Front Immunol ; 9: 1036, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868001

RESUMO

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

5.
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.

7.
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
8.
EBioMedicine ; 6: 222-230, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27211564

RESUMO

Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (<50 and 50-99×10(6)/L respectively), and normal NK cell counts (>100×10(6)/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal.


Assuntos
Imunodeficiência de Variável Comum/classificação , Imunodeficiência de Variável Comum/imunologia , Células Matadoras Naturais/citologia , Linfopenia/epidemiologia , Adulto , Estudos de Coortes , Imunodeficiência de Variável Comum/complicações , Feminino , França/epidemiologia , Humanos , Contagem de Linfócitos , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade
9.
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
10.
Intensive Care Med ; 41(1): 1-11, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25354475

RESUMO

PURPOSE: A specific biomarker of post-ARDS fibroproliferation could be useful in the identification of patients who could benefit from therapies aiming to modulate fibroproliferation such as corticosteroids.The aim of this prospective study was to determine the best threshold of the N-terminal-peptidetype III procollagen (NT-PCP-III) in non-resolving ARDS to validate this threshold according to the outcome. METHODS: Concerning the best threshold of NT-PCP-III, all consecutive patients with a non-resolving ARDS were included if all the following criteria were fulfilled: moderate to severe ARDS lasting for at least 5 days, lung biopsy performed, serum and alveolar NT-PCP-III obtained within 1 week prior to biopsy, and no documented infection contra-indicating the corticosteroids. In the validation cohort part of the study, patients were included at day 7 if they presented a persistent moderate to severe ARDS. RESULTS: Nineteen of 32 patients had fibroproliferatio nonbiopsy. Serum and alveolar NT-PCP-III were higher in patients with fibroproliferation. Using a threshold of 9 µg/L, alveolar NT-PCP-III had the highest accuracy for diagnosing fibroproliferation (sensitivity = 89.5 % and specificity = 92.3 %). Regarding the 51 patients included in the validation cohort, the mortality rate at day 60 was increased in patients presenting an alveolar NT-PCP-III level higher than 9 µg/L (69 vs. 17 %, p < 0.001). The mean alveolar level of NT-PCP-III on day 7 was 8.1-fold higher in nonsurvivors (p = 0.03). CONCLUSIONS: The determination of NT-PCP-III on BAL done at day 7 in persistent ARDS is able to identify patients with fibroproliferation who could be included in a trial of corticosteroids or any other treatment that might help resolve lung fibroproliferation.


Assuntos
Colágeno Tipo III/metabolismo , Glucocorticoides/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Idoso , Biomarcadores/metabolismo , Biópsia , Líquido da Lavagem Broncoalveolar/química , Feminino , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fibrose Pulmonar/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo
11.
Biomed Res Int ; 2014: 653161, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25243172

RESUMO

The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, P < 0.0001), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD (P < 0.01) and vascular IUGR (P < 0.05). sMIC detection was associated with bilateral early diastolic uterine notches (P = 0.037), thrombocytopenia (P = 0.03), and high proteinuria (P = 0.03) in PE and with the vascular etiology of IUGR (P = 0.0038). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.


Assuntos
Antígenos de Histocompatibilidade Classe I/sangue , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/epidemiologia , Adulto , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/epidemiologia , Antígenos de Histocompatibilidade Classe I/farmacologia , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK/análise , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Gravidez , Proteinúria/sangue , Proteinúria/epidemiologia , Trombocitopenia/sangue , Trombocitopenia/epidemiologia , Adulto Jovem
12.
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
14.
PLoS One ; 7(12): e50446, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23236375

RESUMO

RATIONALE: Natural killer cells, as a major source of interferon-γ, contribute to the amplification of the inflammatory response as well as to mortality during severe sepsis in animal models. OBJECTIVE: We studied the phenotype and functions of circulating NK cells in critically-ill septic patients. METHODS: Blood samples were taken <48 hours after admission from 42 ICU patients with severe sepsis (n = 15) or septic shock (n = 14) (Sepsis group), non-septic SIRS (n = 13) (SIRS group), as well as 21 healthy controls. The immuno-phenotype and functions of NK cells were studied by flow cytometry. RESULTS: The absolute number of peripheral blood CD3-CD56(+) NK cells was similarly reduced in all groups of ICU patients, but with a normal percentage of NK cells. When NK cell cytotoxicity was evaluated with degranulation assays (CD107 expression), no difference was observed between Sepsis patients and healthy controls. Under antibody-dependent cell cytotoxicity (ADCC) conditions, SIRS patients exhibited increased CD107 surface expression on NK cells (62.9[61.3-70]%) compared to healthy controls (43.5[32.1-53.1]%) or Sepsis patients (49.2[37.3-62.9]%) (p = 0.002). Compared to healthy (10.2[6.3-13.1]%), reduced interferon-γ production by NK cells (K562 stimulation) was observed in Sepsis group (6.2[2.2-9.9]%, p<0.01), and especially in patients with septic shock. Conversely, SIRS patients exhibited increased interferon-γ production (42.9[30.1-54.7]%) compared to Sepsis patients (18.4[11.7-35.7]%, p<0.01) or healthy controls (26.8[19.3-44.9]%, p = 0.09) in ADCC condition. CONCLUSIONS: Extensive monitoring of the NK-cell phenotype and function in critically-ill septic patients revealed early decreased NK-cell function with impaired interferon-γ production. These results may aid future NK-based immuno-interventions. TRIAL REGISTRATION: NTC00699868.


Assuntos
Células Matadoras Naturais/imunologia , Sepse/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Idoso , Estado Terminal , Citocinas/sangue , Feminino , Humanos , Células Matadoras Naturais/citologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Sepse/sangue , Sepse/mortalidade , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/mortalidade
15.
Crit Care Med ; 40(12): 3162-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22971588

RESUMO

OBJECTIVE: The mechanisms involved in cytomegalovirus reactivation in critically ill patients who were previously immunocompetent are still unknown. The current study was designed to evaluate the possible role of natural killer cells in the reactivation of cytomegalovirus in these patients. DESIGN: Prospective observational. SETTING: : A medical intensive care unit of a university hospital. PATIENTS: Fifty-one subjects, including 15 patients who experienced cytomegalovirus reactivation (cases) during their intensive care unit stay and 15 patients who matched intensive care unit controls, selected from a cohort of consecutive nonimmunocompromised intensive care unit patients, as well as healthy controls. INTERVENTIONS: Tests included weekly systematic immunomonitoring and routine screening for cytomegalovirus infection until discharge from the intensive care unit or death. The immunophenotype and functions of natural killer cells were performed by flow cytometry, and serum levels of pro- and anti-inflammatory cytokines were determined by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: The overall occurrence of cytomegalovirus reactivation in the cohort was 27%. No differences of natural killer cell effector functions were observed at admission between cases and controls. Instead, before cytomegalovirus reactivation, the ability of natural killer cells to secrete interferon-γ was significantly reduced in cases as compared with controls upon stimulation with antibody-coated target cells (p = .029) and with K562 cell stimulation (p = .029). No phenotypic or quantitative differences were observed between cases and controls. Cases exhibited higher levels of interleukin 10 (p = .031) and interleukin 15 (p = .021) than controls before cytomegalovirus reactivation. CONCLUSIONS: Impaired natural killer cell function with reduced interferon-γ secretion precedes the occurrence of cytomegalovirus reactivation among previously immunocompetent critically ill patients.


Assuntos
Estado Terminal , Citomegalovirus/fisiologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Viral , Idoso , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
Front Immunol ; 3: 239, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22891066

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8(+) T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.

17.
Proc Natl Acad Sci U S A ; 108(51): 20684-9, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-22143786

RESUMO

Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (<1 µm, annexin V positive without DNA and no histones) and another larger (1-3 µm) apoptotic body-like particles containing nuclear fragments and histones, representing apoptotic bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1α and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1α precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1α-dependent but IL-1ß-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1α and, therefore, constitute a unique mechanism for sterile inflammation.


Assuntos
Células Endoteliais/citologia , Interleucina-1alfa/metabolismo , Animais , Apoptose , Autoimunidade , Micropartículas Derivadas de Células , Quimiocina CCL2/metabolismo , Histonas/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-8/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologia
18.
J Biomed Biotechnol ; 2011: 986491, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21629707

RESUMO

Severe sepsis and septic shock are still deadly conditions urging to develop novel therapies. A better understanding of the complex modifications of the immune system of septic patients is needed for the development of innovative immunointerventions. Natural killer (NK) cells are characterized as CD3(-)NKp46(+)CD56(+) cells that can be cytotoxic and/or produce high amounts of cytokines such as IFN-γ. NK cells are also engaged in crosstalks with other immune cells, such as dendritic cells, macrophages, and neutrophils. During the early stage of septic shock, NK cells may play a key role in the promotion of the systemic inflammation, as suggested in mice models. Alternatively, at a later stage, NK cells-acquired dysfunction could favor nosocomial infections and mortality. Standardized biological tools defining patients' NK cell status during the different stages of sepsis are mandatory to guide potential immuno-interventions. Herein, we review the potential role of NK cells during severe sepsis and septic shock.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Modelos Imunológicos , Sepse/imunologia , Sepse/patologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Animais , Humanos , Camundongos
19.
J Immunol ; 186(9): 5273-83, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21441448

RESUMO

Leukocyte adhesion deficiency type III is a recently described condition involving a Glanzmann-type bleeding syndrome and leukocyte adhesion deficiency. This was ascribed to a defect of the FERMT3 gene resulting in abnormal expression of kindlin-3, a protein expressed in hematopoietic cells with a major role in the regulation of integrin activation. In this article, we describe a patient with a new mutation of FERMT3 and lack of kindlin-3 expression in platelets and leukocytes. We assayed quantitatively the first steps of kindlin-3-defective leukocyte adhesion, namely, initial bond formation, bond strengthening, and early spreading. Initial bond formation was readily stimulated with neutrophils stimulated by fMLF, and neutrophils and lymphocytes stimulated by a phorbol ester or Mn(2+). In contrast, attachment strengthening was defective in the patient's lymphocytes treated with PMA or Mn(2+), or fMLF-stimulated neutrophils. However, attachment strengthening was normal in patient's neutrophils treated with phorbol ester or Mn(2+). In addition, the patient's T lymphocytes displayed defective integrin-mediated spreading and a moderate but significant decrease of spreading on anti-CD3-coated surfaces. Patient's neutrophils displayed a drastic alteration of integrin-mediated spreading after fMLF or PMA stimulation, whereas signaling-independent Mn(2+) allowed significant spreading. In conclusion, the consequences of kindlin-3 deficiency on ß(2) integrin function depend on both cell type and the stimulus used for integrin activation. Our results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion.


Assuntos
Plaquetas/metabolismo , Síndrome da Aderência Leucocítica Deficitária/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Neutrófilos/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Adesão Celular/genética , Separação Celular , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Immunoblotting , Integrina alfa2/genética , Integrinas/metabolismo , Síndrome da Aderência Leucocítica Deficitária/metabolismo , Síndrome da Aderência Leucocítica Deficitária/fisiopatologia , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Clin Immunol ; 135(1): 26-32, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20093094

RESUMO

Killer Ig-like receptors (KIRs) are MHC class I-specific receptors expressed by Natural Killer (NK) and T cell subsets. KIRs either inhibit (KIR-L) or activate (KIR-S) lymphocyte functions. Inhibitory KIR2DL1 and activating KIR2DS1 share ligand specificity for the HLA-C2 group, consistent with their almost identical extracytoplasmic domain. This homology hampered the distinction between KIR2DL1 and KIR2DS1. We report here the characterization of the KIR2DS1(+) subsets among primary human NK and T cells. Regardless of the host HLA-C genotype, around 10% of circulating NK cells expressed KIR2DS1 in absence of KIR2DL1. In HLA-C2 individuals, KIR2DS1 was not able to induce NK cell education (i.e., the acquisition of NK cell competence) nor to interfere with KIR2DL1-induced NK cell education. KIR2DS1 was also present on rare oligoclonal TCRalphabeta(+)CD8alpha(+) and TCRalphabeta(+)CD4(-)CD8(-) subsets. As KIR2DS1 has been associated with autoimmunity and hematopoietic stem cell transplantation, these results pave the way to dissect the function of KIR2DS1 in these clinical conditions.


Assuntos
Antígenos HLA-C/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/biossíntese , Linfócitos T/imunologia , Animais , Linhagem Celular , DNA/química , DNA/genética , Citometria de Fluxo , Genótipo , Humanos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/imunologia , Camundongos , Receptores KIR/genética , Receptores KIR/imunologia
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