The presence of an effector CD4 T cell population at birth

La réponse immunitaire chez le nouveau-né est caractérisée par une protection limitée ( < 6 mois) , les réponses Ab faibles ( < 12 à 24 mois) , et le réponses des cellules T restreintes caractérisé par un biaisée vers des réponses Th2. Les réponses de l'IFN minimale produisant cellules T ne parviennent pas à se défendre contre l'infection microbienne contribuant à l'estimation de l'OMS que les enfants 2M entre 1-6 mois meurent chaque année d'infections évitables . Le développement des cellules T humaine commence à 10 semaines de gestation (GW) , où les cellules puis l'évacuation du thymus pour coloniser 1 périphérie. Environ 20 gw , désoxynucléotidyltransférase terminale expression est lancée , conférant la diversité des TCR maximum. [La] Grossesse exige l'établissement d'un état de tolérance foeto-maternelle entre la mère et antigènes foetaux à l'interface du foetus . De même, le foetus se développe des cellules T régulatrices aux antigènes maternels. Par conséquent à la naissance et à l'absence de toute infection foetale , le compartiment des cellules ' contient supposément cellules T naïves seulement et réglementaires . Ici nous avons caractérisé compartiment de cellules CD4 + T périphérique du nouveau-né en fonction de sa maturité et de son potentiel à développer ou à obtenir une diversité de fonctions effectrices .CD127hi et d'expression CD12710 sépare les cellules T CD4 + classiques de Tregs respectivement . En plus de cellules T et CD127hi CD127lowFoxp Tregs , nous avons identifié une petite population de cellules CD45RO + CD127hi dépourvu d'expression Foxp3 dans le sang de cordon . Ces cellules représentent environ 3% de la population totale de lymphocytes CD4 + et sont toujours associés à tous les échantillons de sang de cordon ( n = 10) , et l'absence de toute infection naturelle rapporté du foetus. À la suite de l'anti-CD3 et anti- CD28 stimulation , et à l'intérieur de ces 'cellules produites heures Thl et Th2 cytokines effectrices de l'IFN- y , IL-13 et IL-4, mais l'IL - 22 et IL- 17 a pas été détecté . La présence d' adultes Th sous-ensemble associé chimiokines récepteurs ( CXCR3 , CCR4 , CCR6 ) dans le sang du cordon parrainé la sous-ensembles Th putatifs classiques de réponse d cytokine et a montré que la réponse IFN a pu être isolé à CXCR3 + , alors que l'IL- 4 et IL- 13 étaient produit sur tous les sous-ensembles exprimait une CCR associé Th de sous-ensemble . Comparaisons directes d'analyse de puces à ADN de sang de cordon par rapport aux sous-ensembles putatif T Th adulte défini des sous-ensembles ont révélé des signatures de l'adulte comme distinctes , ainsi qu'un degré de plasticité à partager les fonctions Th2 like tels que IL-4 et IL-13 production . La preuve éclatante que le compartiment des cellules T matures existe à la naissance soulève la question de savoir comment la mémoire T classique se développe et quels antigènes stimulent une réponse. Dans l'ensemble, ces cellules T mémoires peuvent également influer sur le développement des réponses des lymphocytes T en début de vie et offrir un aperçu important pour la conception de nouveaux et futurs vaccins néonatals.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Stem-Loop Silencing Reveals that a Third Mitochondrial DNA Polymerase, POLID, Is Required for Kinetoplast DNA Replication in Trypanosomes▿

Kinetoplast DNA (kDNA), the mitochondrial genome of trypanosomes, is a catenated network containing thousands of minicircles and tens of maxicircles. The topological complexity dictates some unusual features including a topoisomerase-mediated release-and-reattachment mechanism for minicircle replication and at least six mitochondrial DNA polymerases (Pols) for kDNA transactions. Previously, we identified four family A DNA Pols from Trypanosoma brucei with similarity to bacterial DNA Pol I and demonstrated that two (POLIB and POLIC) were essential for maintaining the kDNA network, while POLIA was not. Here, we used RNA interference to investigate the function of POLID in procyclic T. brucei. Stem-loop silencing of POLID resulted in growth arrest and the progressive loss of the kDNA network. Additional defects in kDNA replication included a rapid decline in minicircle and maxicircle abundance and a transient accumulation of minicircle replication intermediates before loss of the kDNA network. These results demonstrate that POLID is a third essential DNA Pol required for kDNA replication. While other eukaryotes utilize a single DNA Pol (Pol γ) for replication of mitochondrial DNA, T. brucei requires at least three to maintain the complex kDNA network

Perspective: A novel prognostic for sickle cell disease

Sickle hemoglobin (α2βS2) polymerization drives disease pathophysiology in sickle cell anemia. Fetal hemoglobin (α2γ2) restricts disease severity by inhibiting the polymerization of sickle hemoglobin in a concentration-dependent manner. Clinical decision-making relies on diagnostic technologies evaluating fetal hemoglobin as mean percent or mean quantity in blood. Limitation of this approach is exemplified by patients with significant high fetal hemoglobin levels and severe disease, suggesting that fetal hemoglobin is unevenly distributed across F-cells. Therefore, determination of fetal hemoglobin/F-cell would provide a new paradigm for ascertaining prognosis and response to fetal hemoglobin-inducing agents. Measurement of fetal hemoglobin/F-cell, ultimately adapted to widespread standardized analytical use, is a promising fetal hemoglobin-related prognostic approach to monitor the severity of sickle cell disease and the best “phenotype” to follow when developing new candidate fetal hemoglobin inducers or titrating hydroxyurea in treated sickle cell patients

B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection mediated by the virulence factor IpaD

International audienceShigella is a gram-negative enteroinvasive bacterium and the causative agent of bacillary dysentery, an acute recto-colitis. Antibody-mediated natural immunity to Shigella requires several episodes of infection to get primed and is short-lasting, suggesting that the B cell response is functionally impaired. Here we show that upon ex vivo infection of human colonic tissue, invasive S. flexneri interacts with and invades B lymphocytes. We observe the induction of a type three secretion apparatus (T3SA)-dependent B cell death in vitro, both in lamina propria B lymphocytes and the human CL-01 B cell line. This cell death and the parallel reduction of the B cell pool can also be observed in an in vivo mouse infection model. Intriguingly, Shigella-induced B cell death does not require bacterial invasion or injection of virulence effectors via the T3SA in vitro. Instead, the virulence factor IpaD triggers mitochondrial B cell apoptosis in the presence of bacterial co-signals that render B lymphocytes prone to die. We provide evidence that IpaD binds to and induces apoptosis via TLR2, a signaling pathway that has thus far only been considered as a mitogenic stimulus for B lymphocytes. Apoptotic B lymphocytes in close contact with Shigella displaying IpaD are also detected in isolated lymphoid follicles of rectal biopsies of naturally-infected individuals. These findings reveal a novel mechanism of T3SA action to induce B cell death by the binding of a virulence factor and reveal an efficient strategy by which entero-invasive pathogens could impair the priming of a protective immune response

Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults

Background. Human immunodefciency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with eflective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. Methods. We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/μ L and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Results. Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed defcits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-coactivator 1a-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Conclusions. Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profles, subclinical defcits in physical function, and persistent inflammation and immune activation. Identifying biomarker profles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions

Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations

Abstract Background Genome wide association studies of patients with European descent have identified common variants associated with risk of reduced estimated glomerular filtration rate (eGFR). A panel of eight variants were selected to evaluate their association and prevalence in a Saudi Arabian patient cohort with chronic kidney disease (CKD). Methods Eight genetic variants in four genes (SHROOM3, MYH9, SLC7A9, and CST3) were genotyped in 160 CKD patients and 189 ethnicity-matched healthy controls. Genetic variants were tested for association with the development of CKD (eGFR < 60 ml/min/1.73m2) and effects were compared with results obtained from 133,413 participants in the CKD genetics consortium. Multivariable regression was used to evaluate the role of these eight variants in improving prediction of CKD development. Results All eight variants were present in Saudi populations with minor allele frequency ranging from 16 to 46%. The risk variant in all four genes demonstrated the same direction of effect as observed in European populations. One variant, rs4821480, in MYH9 was significantly associated with increased risk of development of CKD (OR = 1.69, 95% CI 1.22–2.36, P = 0.002), but the additional variants were not statistically significant given our modest sample size. Conclusions CKD risk variants identified in European populations are present in Saudis. We did not find evidence to suggest heterogeneity of effect size compared to previously published estimates in European populations. Multivariable logistic regression analysis showed a statistically significant improvement in predicting the CKD using models with either FGF23 and vitamin D or FGF23, vitamin D level, and MYH9 genotypes (AUC = 0.93, 95% CI 0.90–0.95, P <  0.0001)

Additional file 1: of Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations

Table S1. One-way ANOVA comparing the various Biochemical parameters in patients stratified for ESRD, T2D and HTN. Table S2. Correlation of biochemical parameters stratified by CKD, Type 2 Diabetes and Hypertension status. (DOCX 21 kb

Plasmacytoid dendritic cells engagement by influenza vaccine as a surrogate strategy for driving T-helper type 1 responses in human neonatal settings.

International audienceThe elicitation of T-helper type 1 (Th1) cellular immunity to eradicate intracellular pathogens is a challenging task because of the interleukin 12 (IL-12) deficit observed in early infancy. Screening cord blood responses to various pediatric vaccines and Toll-like receptor (TLR) agonists for innate responses and CD4(+) T-cell differentiation. We identified that nonadjuvanted inactivated trivalent influenza vaccine (TIV) was able to cosignal T cells for the production of interferon γ (IFN-γ) in a neonatal setting. This process includes the mobilization of neonatal plasmacytoid dendritic cells (pDCs) as antigen-presenting cells (APCs) that efficiently engage Th1 cells in an IL-12-independent but type I IFN-dependent manner. In addition, cord blood pDCs efficiently cross-presented antigen to CD8(+) T cells. Importantly, activation by TIV mainly requires TLR7; however, R848/TLR7- and CpGB/TLR9-activated pDCs, which poorly produced IFN-α, induce neonatal Th2 responses. TLR pathway engagement in pDCs is necessary but not sufficient for a successful neonatal Th1 outcome. We provide evidence of a mature and functional neonatal immune system at the level of APCs and T cells and propose to implement the IFN-α/IFN-γ axis in pediatric vaccination as a surrogate for the defective IL-12/IFN-γ axis