RESUMO
After the first wave of the COVID-19 pandemic, during which the severity of the disease in certain countries was attributed to a lack of basic education of the inhabitants, the authors of this paper initiated a literature review of educational trajectories, health, and ageing well. The findings strongly demonstrate that alongside genetics, the affective and educational family environment, as well as the general environment, greatly interact starting from the very first days of life. Thus, epigenetics plays a major role in the determination of health and disease [DOHAD] in the first 1,000 days of life as well as in the characterization of gender. Other factors such as socio-economic level, parental education, schooling in urban or rural areas, also play a major role in the differential acquisition of health literacy. This determines adherence (or lack thereof) to healthy lifestyles, risky behaviours, substance abuse, but also compliance with hygiene rules, and adherence to vaccines and treatments. The combination of all these elements and lifestyle choices facilitates the emergence of metabolic disorders (obesity, diabetes), which promote cardiovascular and kidney damage, and neurodegenerative diseases, explaining that the less well educated have shorter survival and spend more years of life in disability. After having demonstrated the impact of the educational level on health and longevity, the members of this inter-academic group propose specific educational actions at three levels: (1) teachers and health professionals, (2) parents, (3) the public, emphasizing that these crucial actions can only be carried out with the unfailing support of state and academic authorities.
Assuntos
COVID-19 , Envelhecimento Saudável , Humanos , Acontecimentos que Mudam a Vida , Pandemias , COVID-19/epidemiologia , Escolaridade , Educação em SaúdeRESUMO
Accumulating evidence majorly implicates immune dysfunction in the etiology of psychotic disorders. In particular, altered numbers and functions of natural killer (NK) cells have been described in psychosis, but interpretation has often been confounded by a number of biases, including treatment. Eighty-one first-episode psychosis (FEP) patients who subsequently received a diagnosis of either schizophrenia (SZ; n = 30) or bipolar disorder (BP; n = 31) over a five-year follow-up period were investigated for their NK cell phenotype and compared to 61 healthy controls (HCs). We found a similar proportion of CD3-CD56+ NK cells in FEP patients and HCs. The frequency of NK cells expressing the late cell activation marker HLA-DR was significantly increased in FEP patients compared to HCs, especially in patients with BP (p < 0.0001) and, to a lesser degree, in patients with SZ (p = 0.0128). Interestingly, the expression of the activating NKG2C receptor, known to be associated with infections, was higher in patients with SZ and BP than in HCs (p < 0.0001) and correlated with HLA-DR expression, altogether defining adaptive NK cells. In terms of NK cell function, we observed a suppressed capacity of SZ-derived NK cells to mount cytotoxic responses in the presence of target cells, while NK cells from patients with BP show an inability to produce IFN-γ, a cytokine pivotal to NK function. This study strongly suggests major dysfunction of NK cells in FEP with functioning impairment correlated with psychotic, manic, and depressive symptoms in subsequently diagnosed patients with SZ and BP.
Assuntos
Transtorno Bipolar , Transtornos Psicóticos , Esquizofrenia , Humanos , Imunidade Inata , Células Matadoras NaturaisRESUMO
The COVID-19 pandemic occurred in the context of a dramatic decline in support for biological and health research in France. An analysis of resources allocated to this sector shows that the credits in 2020 correspond to only 17.2 % of the total credits allocated to research, the lowest ratio inat least 15 years. Another weakness in the system of support for hospital research is the way funds from the health insurance system are allocated. To bring it into line with international best practices, the task of allocating these funds should be entrusted to a "Hospital Research Orientation Council", which should also be involved in the implementation of national research programming. Another article deals with the organization of research. Recommendations are also made to improve the functioning of the research system at the local level, particularly in university hospitals, and at the national level.
RESUMO
Aspergillus fumigatus is an opportunistic human fungal pathogen that sheds galactosaminogalactan (GG) into the environment. Polymorphonuclear neutrophils (PMNs) and NK cells are both part of the first line of defense against pathogens. We recently reported that GG induces PMN apoptosis. In this study, we show that PMN apoptosis occurs via a new NK cell-dependent mechanism. Reactive oxygen species, induced by the presence of GG, play an indispensable role in this apoptotic effect by increasing MHC class I chain-related molecule A expression at the PMN surface. This increased expression enables interaction between MHC class I chain-related molecule A and NKG2D, leading to NK cell activation, which in turn generates a Fas-dependent apoptosis-promoting signal in PMNs. Taken together, our results demonstrate that the crosstalk between PMNs and NK cells is essential to GG-induced PMN apoptosis. NK cells might thus play a role in the induction of PMN apoptosis in situations such as unexplained neutropenia or autoimmune diseases.
Assuntos
Apoptose/imunologia , Aspergillus fumigatus/imunologia , Polissacarídeos Fúngicos/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Neutrófilos/imunologia , Fatores de Virulência/imunologia , Apoptose/efeitos dos fármacos , Aspergillus fumigatus/patogenicidade , Feminino , Polissacarídeos Fúngicos/toxicidade , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Neutrófilos/patologia , Espécies Reativas de Oxigênio/imunologia , Fatores de Virulência/farmacologiaRESUMO
Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV(+) patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.
Assuntos
Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Citomegalovirus/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Transplante de Fígado/efeitos adversos , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/etiologia , Adulto , Idoso , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Citocinas/metabolismo , Citomegalovirus/genética , Feminino , Humanos , Imunofenotipagem , Células Matadoras Naturais/virologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Adulto JovemRESUMO
With an array of activating and inhibitory receptors, natural killer (NK) cells are involved in the eradication of infected, transformed, and tumor cells. NKp44 is a member of the natural cytotoxicity receptor family, which is exclusively expressed on activated NK cells. Here, we identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. The sharply decreased NK lysis activity induced by anti-NKp44L antibodies directly demonstrates the role of NKp44L in cytotoxicity. Taken together, these results show that NKp44L could be critical for NK cell-mediated innate immunity. The identification and cellular distribution of NKp44L highlight the role of this self-molecule as a danger signal to alert the NK cell network.
Assuntos
Citotoxicidade Imunológica/genética , Proteínas de Ligação a DNA/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Motivos de Aminoácidos , Anticorpos Neutralizantes/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Biblioteca Gênica , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Ligantes , Ativação Linfocitária , Receptor 2 Desencadeador da Citotoxicidade Natural/genética , Especificidade de Órgãos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Estrutura Terciária de Proteína , Técnicas do Sistema de Duplo-HíbridoRESUMO
The successes of anti-retroviral treatments against HIV are limited today by the cost and toxicity of lifelong administration. An innovative therapeutic strategy has been proposed to boost the immune system of infected patients with HIV vaccines and to help limit the use of anti-retroviral treatments. This perspective article reviews the crucial questions raised by such a strategy and the main international efforts that are already set up to provide rapid answers--in particular, a not-for-profit international network that is dedicated to the development of therapeutic immunization programmes against HIV.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/terapia , Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/economia , Custos e Análise de Custo , Saúde Global , Infecções por HIV/imunologia , Humanos , Programas de Imunização/normas , Cooperação InternacionalRESUMO
The human body normally lives in symbiosis with a considerable microscopic environment present on all interfaces with the external environment; it hosts ten times more microbes (microbiota) that it has somatic or germ cells, representing a gene diversity (microbiome) 100-150 times higher than the human genome. These germs are located mainly in the gut, where they represent a mass of about one kilogram. The primary colonization of the gastrointestinal tract depends on the delivery route, the bacterial flora rewarding then depending on the environment, food hygiene, medical treatments. The intestinal microbiota plays an important role in the maturation of the immune system and in different physiological functions: digestion of polysaccharides, glycosaminoglycans and glycoproteins, vitamins biosynthesis, bile salt metabolism of some amino acids and xenobiotics. Quantitative and qualitative changes in the microbiota are observed in a wide range of diseases: obesity, colorectal cancer, liver cancer, inflammatory bowel disease, autoimmune diseases, allergies... pharmacobiotics aim to modify the intestinal microbiota in a therapeutic goal and this by various means: prebiotics, probiotics, antibiotics or fecal transplants. Intestinal flora also plays a direct role in the metabolism of certain drugs and the microbiota should be considered as a predictive parameter of response to some chemotherapies.
Assuntos
Microbioma Gastrointestinal , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Neoplasias Hepáticas/microbiologia , Obesidade/microbiologiaRESUMO
DNA sequencing technologies have advanced at an exponential rate in recent years: the first human genome was sequenced in 2001 after many years of effort by dozens of international laboratories at a cost of tens of millions of dollars, while in 2013 a genome can be sequenced within 24 hours for a few hundred dollars (exome sequencing takes only a few hours). More and more hospital laboratories are acquiring new high-throughput sequencing devices ("next-generation sequencers", NGS), allowing them to analyze tens or hundreds of genes, or even the entire exome. This is having a major impact on medical concepts and practices, especially with respect to genetics and oncology. This ability to search for mutations simultaneously in a large number of genes is finding applications in the diagnosis of Mendelian diseases (including at birth), routine screening for heterozygotes, and pre-conception diagnosis. NGS is now sufficiently sensitive to analyze circulating fetal DNA in maternal blood (cell-free fetal DNA, cffDNA), enabling applications such as non invasive diagnosis of fetal sex (and X-linked diseases), fetal rhesus among rhesus-negative women, trisomy and, in the near future, Mendelian mutations. Data on multifactorial diseases are still preliminary, but it should soon be possible to identify "strong" factors of genetic predisposition that have so far been beyond the scope of genome-wide association studies (GWAS). In the field of constitutional oncogenetics, NGS can also be used for simultaneous analysis of genes involved in " hereditary " cancers (21 breast cancer genes, 6 colon cancer genes, etc.). More generally, NGS can identify all genomic abnormalities (deletions, translocations, mutations) in a given malignant tissue (hemopathy or solid tumor), and has the potential to distinguish between important mutations (those that drive tumor progression) from " bystander " or accessory mutations, and also to identify "druggable" mutations amenable to targeted therapies (e.g. imatinib and Bcr/Abl rearrangement; verumafemib and the BRAF V600E mutation). Systematic sequencing of all the genes involved in drug metabolism and responsiveness will lead to individualized pharmacogenetics. Finally, sequencing of the tumoral and constitutional genomes, identfication of somatic mutations, and detection of pharmacogenetic variants will open up the era of personalized medicine. The first results of these targeted therapeutic indications show a gain in the duration of remission and survival, although the cost-effectiveness of these approaches remains to be determined. Finally, this huge capacity for genome sequencing raises a number of regulatory and ethical issues.
Assuntos
Análise Mutacional de DNA , Testes Genéticos , Medicina de Precisão , Análise de Sequência de DNA , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias/genética , Gravidez , Diagnóstico Pré-Implantação , Diagnóstico Pré-NatalRESUMO
BACKGROUND: The induction of neutralizing antibodies against conserved regions of the human immunodeficiency virus type 1 (HIV-1) envelope protein is a major goal of vaccine strategies. We previously identified 3S, a critical conserved motif of gp41 that induces the NKp44L ligand of an activating NK receptor. In vivo, anti-3S antibodies protect against the natural killer (NK) cell-mediated CD4 depletion that occurs without efficient viral neutralization. METHODS: Specific substitutions within the 3S peptide motif were prepared by directed mutagenesis. Virus production was monitored by measuring the p24 production. Neutralization assays were performed with immune-purified antibodies from immunized mice and a cohort of HIV-infected patients. Expression of NKp44L on CD4(+) T cells and degranulation assay on activating NK cells were both performed by flow cytometry. RESULTS: Here, we show that specific substitutions in the 3S motif reduce viral infection without affecting gp41 production, while decreasing both its capacity to induce NKp44L expression on CD4(+) T cells and its sensitivity to autologous NK cells. Generation of antibodies in mice against the W614 specific position in the 3S motif elicited a capacity to neutralize cross-clade viruses, notable in its magnitude, breadth, and durability. Antibodies against this 3S variant were also detected in sera from some HIV-1-infected patients, demonstrating both neutralization activity and protection against CD4 depletion. CONCLUSIONS: These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4(+) T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Anticorpos Anti-HIV/sangue , Proteína gp41 do Envelope de HIV/genética , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Adolescente , Adulto , Substituição de Aminoácidos , Animais , Anticorpos Neutralizantes/sangue , Contagem de Linfócito CD4 , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Mutação de Sentido Incorreto , Adulto JovemRESUMO
Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C(+) CD56(dim) NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C(+) CD56(dim) NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C(+) CD56(dim) NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.
Assuntos
Seleção Clonal Mediada por Antígeno , Citomegalovirus/imunologia , Hepatite Crônica/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/metabolismo , Adulto , Anticorpos Antivirais/sangue , Autoantígenos/imunologia , Antígeno CD56/metabolismo , Diferenciação Celular , Processos de Crescimento Celular , Células Cultivadas , Citocinas/metabolismo , Citomegalovirus/patogenicidade , Feminino , Regulação da Expressão Gênica/imunologia , Hepatite Crônica/sangue , Hepatite Crônica/virologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/patologia , Subpopulações de Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores KIR2DL2/imunologia , Receptores KIR2DL2/metabolismo , Antígenos HLA-ERESUMO
Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance.
Assuntos
Infecções por Alphavirus/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Antígeno CD56/imunologia , Febre de Chikungunya , Vírus Chikungunya/imunologia , Feminino , Antígenos HLA-C/imunologia , Humanos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores de Células Matadoras Naturais/análiseRESUMO
Normal chondrocytes display susceptibility to lysis by natural killer (NK) cells and this phenomenon may play a role in some inflammatory cartilage disorders. The mechanisms of chondrocyte recognition and killing by NK cells remain unclear. Using flow cytometry and immunohistochemical staining we found that normal human articular chondrocytes constitutively express a ligand for NKp44, one of stimulatory NK cell receptors involved in recognition and killing of target cells. Expression of NKp44 ligand by normal articular chondrocytes is not involved in their killing by unstimulated NK cells; however, it is responsible for anti-chondrocyte cytotoxicity mediated by long-term activated NK cells. Thus, expression of NKp44 ligand may play a role in chondrocyte destruction in course of chronic inflammatory cartilage disorders.
Assuntos
Cartilagem/imunologia , Condrócitos/metabolismo , Células Matadoras Naturais/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Cartilagem/citologia , Células Cultivadas , Criança , Pré-Escolar , Pé Torto Equinovaro , Citotoxicidade Imunológica/imunologia , Humanos , Lactente , Leucócitos Mononucleares/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/biossíntese , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismoRESUMO
Human NK cells comprise two main subsets, CD56(bright) and CD56(dim) cells, which differ in function, phenotype, and tissue localization. To further dissect the differentiation from CD56(bright) to CD56(dim) cells, we performed ex vivo and in vitro experiments demonstrating that the CD56(bright)CD16(+) cells are an intermediate stage of NK cell maturation. We observed that the maximal frequency of the CD56(bright)CD16(+) subset among NK cells, following unrelated cord blood transplantation, occurs later than this of the CD56(bright)CD16(-) subset. We next performed an extensive phenotypic and functional analysis of CD56(bright)CD16(+) cells in healthy donors, which displayed a phenotypic intermediary profile between CD56(bright)CD16(-) and CD56(dim)CD16(+) NK cells. We also demonstrated that CD56(bright)CD16(+) NK cells were fully able to kill target cells, both by Ab-dependent cell cytotoxicity (ADCC) and direct lysis, as compared with CD56(bright)CD16(-) cells. Importantly, in vitro differentiation experiments revealed that autologous T cells specifically encourage the differentiation from CD56(bright)CD16(-) to CD56(bright)CD16(+) cells. Finally, further investigations performed in elderly patients clearly showed that both CD56(bright)CD16(+) and CD56(dim)CD16(+) mature subsets were substantially increased in older individuals, whereas the CD56(bright)CD16(-) precursor subset was decreased. Altogether, these data provide evidence that the CD56(bright)CD16(+) NK cell subset is a functional intermediate between the CD56(bright) and CD56(dim) cells and is generated in the presence of autologous T CD3(+) cells.
Assuntos
Antígeno CD56/análise , Diferenciação Celular/imunologia , Células Matadoras Naturais/citologia , Idoso , Complexo CD3 , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Proteínas Ligadas por GPI/imunologia , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Receptores de IgG/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Doadores de TecidosRESUMO
About one-quarter of deaths worldwide (nearly 13 million per year) are still directly related to infectious diseases. Many new infections have emerged since the end of the 20th century and others will continue to do so. Human beings, like other animals, are not all equal with respect to their susceptibility to infection. Since the 1930s, numerous epidemiological studies have shown that host genetic factors play a major role in susceptibility and resistance to infections. Studies of Mendelian genetics and genetic epidemiology based on association studies, now using high-speed typing of anonymous polymorphic markers, can detect genes or loci that influence an individual's response to a particular germ. Different cases of susceptibility or resistance to viral, bacterial, fungal and parasitic infections will be used to illustrate the importance of genetic factors in the diagnosis of clinical manifestations and their prevention, characterization of host immune responses, and their influence on evolutionary biology. With different phenotypes associated with genetic polymorphisms, and new genomic techniques, the genetics of infectious diseases is entering a new era, raising questions of medical practice, ethics, and public and industrial policies.
Assuntos
Doenças Transmissíveis/genética , Técnicas Genéticas , Animais , Exoma/genética , Predisposição Genética para Doença , Humanos , Análise da Randomização Mendeliana , Análise de Sequência de DNA/métodosRESUMO
Sarcoidosis is characterized by extensive local inflammation (granuloma, cytokine secretion) associated with anergy (poor response to antigens in vitro and in vivo). We postulated that this paradoxical situation would correspond to a disequilibrium between effector and regulatory T lymphocytes (T reg cells). We show that CD4+CD25(bright)FoxP3+ cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of patients with active disease. These cells exhibited powerful antiproliferative activity, yet did not completely inhibit TNF-alpha production. Sarcoidosis is therefore associated with a global T reg cell subset amplification whose activity would be insufficient to control local inflammation. At the same time, peripheral T reg cells exert powerful antiproliferative activity that may account for the state of anergy. Altogether, these findings advance our conceptual understanding of immune regulation in a way that resolves the immune paradox of sarcoidosis and permit us to envisage a profound clinical impact of T reg cell manipulation on immunity.
Assuntos
Sarcoidose Pulmonar/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Feminino , Fatores de Transcrição Forkhead/metabolismo , Granuloma/metabolismo , Granuloma/patologia , Humanos , Imunidade Inata , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/biossíntese , Receptores de Antígenos de Linfócitos T/genética , Receptores CXCR3 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/genética , Sarcoidose Pulmonar/metabolismo , Sarcoidose Pulmonar/patologia , Linfócitos T Reguladores/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CD4(+) T cell loss is central to HIV pathogenesis. In the initial weeks post-infection, the great majority of dying cells are uninfected CD4(+) T cells. We previously showed that the 3S motif of HIV-1 gp41 induces surface expression of NKp44L, a cellular ligand for an activating NK receptor, on uninfected bystander CD4(+) T cells, rendering them susceptible to autologous NK killing. However, the mechanism of the 3S mediated NKp44L surface expression on CD4(+) T cells remains unknown. Here, using immunoprecipitation, ELISA and blocking antibodies, we demonstrate that the 3S motif of HIV-1 gp41 binds to gC1qR on CD4(+) T cells. We also show that the 3S peptide and two endogenous gC1qR ligands, C1q and HK, each trigger the translocation of pre-existing NKp44L molecules through a signaling cascade that involves sequential activation of PI3K, NADPH oxidase and p190 RhoGAP, and TC10 inactivation. The involvement of PI3K and NADPH oxidase derives from 2D PAGE experiments and the use of PIP3 and H2O2 as well as small molecule inhibitors to respectively induce and inhibit NKp44L surface expression. Using plasmid encoding wild type or mutated form of p190 RhoGAP, we show that 3S mediated NKp44L surface expression on CD4(+) T cells is dependent on p190 RhoGAP. Finally, the role of TC10 in NKp44L surface induction was demonstrated by measuring Rho protein activity following 3S stimulation and using RNA interference. Thus, our results identify gC1qR as a new receptor of HIV-gp41 and demonstrate the signaling cascade it triggers. These findings identify potential mechanisms that new therapeutic strategies could use to prevent the CD4(+) T cell depletion during HIV infection and provide further evidence of a detrimental role played by NK cells in CD4(+) T cell depletion during HIV-1 infection.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína gp41 do Envelope de HIV/metabolismo , Peróxido de Hidrogênio/metabolismo , Receptor 2 Desencadeador da Citotoxicidade Natural/biossíntese , Fosfatidilinositol 3-Quinases/fisiologia , Motivos de Aminoácidos/fisiologia , Proteínas de Transporte/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , NADPH Oxidases/metabolismo , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: To determine the phenotype and the functionality of natural killer (NK) cells in patients with systemic lupus erythematosus (SLE). METHODS: A total of 94 patients with SLE (91 women and 3 men) were compared with 26 healthy controls. Active SLE was defined by an SLE Disease Activity Index score≥4. Immunologic tests were performed using nonactivated and/or interleukin-2 (IL-2)-activated peripheral blood mononuclear cells. NK cell phenotype was determined by flow cytometry. NK cell natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) were determined by 51Cr release and CD107a degranulation experiments. Intracellular interferon-γ (IFNγ) production by NK cells was evaluated after overnight stimulation with IL-12 and IL-18. IFNα levels were assessed using an antiviral cytopathic bioassay. RESULTS: The absolute NK cell count was decreased in patients with active SLE, but the relative frequencies of total CD3-CD56bright NK cells and CD3-CD56dim NK cells were unaffected. The CD3-CD56dim NK cells in patients with active SLE displayed unique phenotypic characteristics, including significant increases in CD69 and NKG2A and decreased expression of Fcγ receptor type IIIa/CD16, CD8α, and the killer cell immunoglobulin-like receptor (KIR) KIR2DL1/KIR2DS1. Concomitant with these findings, NK cells from SLE patients had lower cytotoxicity but a normal level of ADCC compared with NK cells from healthy controls. There was a significant positive correlation between the increased level of IFNα in the serum and the enhanced frequency of IFNγ+ cells in patients with active SLE (r=0.370, P=0.04). CONCLUSION: NK cells in patients with active SLE display phenotypic and functional features associated with activation. Furthermore, NK cells from patients with active SLE have the capacity to produce large amounts of IFNγ. This could contribute to the dysregulation of the link between innate and adaptive immunity seen in SLE.
Assuntos
Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Complexo CD3/imunologia , Antígeno CD56/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Fenótipo , Receptores de IgG/imunologia , Receptores KIR/imunologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the "recovered" or the "chronic" groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 10(10) viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-alpha mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4(++) but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence.
Assuntos
Infecções por Alphavirus/imunologia , Infecções por Alphavirus/patologia , Artrite Infecciosa/imunologia , Artrite Infecciosa/patologia , Vírus Chikungunya/imunologia , Imunidade Ativa , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Alphavirus/epidemiologia , Artralgia/diagnóstico , Artralgia/imunologia , Artralgia/virologia , Artrite Infecciosa/virologia , Vírus Chikungunya/patogenicidade , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Inflamação/epidemiologia , Inflamação/imunologia , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reunião/epidemiologia , Carga Viral/imunologia , Viremia/diagnóstico , Viremia/imunologia , Viremia/patologia , Adulto JovemRESUMO
In the 19th century, the applications of the scientific discoveries of Louis Pasteur to medicine had difficulty in imposing themselves within the French medical community and its National Academy. Among those concerning infectious diseases, their prevention by hygiene and their etiology by microbes are described here. Louis Pasteur found it difficult to convince and had to fight, to show through the surgical practice of asepsis and examples of infections induced in animal models (anthrax), the modes of transmission of germs and their pathogenicity.
Les applications des découvertes scientifiques de Louis Pasteur à la médecine ont eu du mal à s'imposer au XIX e siècle auprès de la communauté médicale française et de son Académie Nationale. Parmi celles qui concernent les maladies infectieuses, leur prévention par l'hygiène et leur étiologie par les microbes sont ici décrites. Louis Pasteur eut du mal à convaincre et dut combattre, pour montrer à travers la pratique chirurgicale de l'asepsie et des exemples d'infections induites dans des modèles animaux (anthrax), les modalités de transmission des germes et leur pathogénicité.