TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway.

International audiencePolymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient's functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient's PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient's PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency

Supernatant from Bifidobacterium Differentially Modulates Transduction Signaling Pathways for Biological Functions of Human Dendritic Cells

International audienceBACKGROUND:Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, the signaling pathways engaged by probiotics are poorly understood. We have previously reported that a fermentation product from Bifidobacterium breve C50 (BbC50sn) could induce maturation, high IL-10 production and prolonged survival of DCs via a TLR2 pathway. We therefore studied the roles of mitogen-activated protein kinases (MAPK), glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K) pathways on biological functions of human monocyte-derived DCs treated with BbC50sn.METHODOLOGY/PRINCIPAL FINDINGS:DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50sn, lipopolysaccharide (LPS) or Zymosan, with or without specific inhibitors of p38MAPK (SB203580), ERK (PD98059), PI3K (LY294002) and GSK3 (SB216763). We found that 1) the PI3K pathway was positively involved in the prolonged DC survival induced by BbC50sn, LPS and Zymosan in contrast to p38MAPK and GSK3 which negatively regulated DC survival; 2) p38MAPK and PI3K were positively involved in DC maturation, in contrast to ERK and GSK3 which negatively regulated DC maturation; 3) ERK and PI3K were positively involved in DC-IL-10 production, in contrast to GSK3 that was positively involved in DC-IL-12 production whereas p38MAPK was positively involved in both; 4) BbC50sn induced a PI3K/Akt phosphorylation similar to Zymosan and a p38MAPK phosphorylation similar to LPS.CONCLUSION/SIGNIFICANCE:We report for the first time that a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions. These results give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

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Uvéites pédiatriques non infectieuses suivies au CHU de Tours

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Dysidrose palmaire (intérêt d'une étude de cohorte dans la prise en charge des patients)

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Antigènes microbiens et transduction par les voies Toll (implications dans la biologie des cellules dendritiques)

Les cellules dendritiques (DC) constituent une population hétérogène qui fait le lien entre immunité innée et adaptative. Les DC possèdent des Toll like récepteurs (TLR) qui reconnaissent un large spectre de structures microbiennes conservées. Selon le type d exposition bactérienne, le recrutement des TLR et les signaux de transduction induits, le processus de maturation de la DC va conditionner une différenciation lymphocytaire spécifique. Nous avons mis en évidence que le surnageant d une bifidobactérie (BBC50SN) induit une maturation et une survie prolonge e des DC, avec une forte production d IL-10 et une faible production d IL-12. En utilisant des inhibiteurs chimiques, nous avons pu mettre en évidence que le BBC50SN induit des signaux de transduction complexes impliquant NF-KB mais également les mapkinases et la pi3kinase. L étude d un cas de déficit en irak4 a mis en évidence, au niveau des polynucléaires neutrophiles, une voie TLR9 indépendante de irak4 impliquant la pi3k.Dendritic cells (DCs) are heterogenous population which constitute a link between innate and adaptative immunity. DCs express Toll like receptors (TLRs) which recognize large bacterial conserved components. Depending of the bacterial contact, the TLR engagement and the transduction pathway involved, the process of DCs maturation induces the specificity of lymphocyte differentiation. We have described that the supernatant of a bifidobacteria (Bbc50SN) induced DC maturation and a prolonged DC survival with a high IL-10 synthesis and a low IL-12 production. Using chemical inhibitors, we showed that BbC50SN induced complex transduction pathway including NF-kB but also mapkinases and Pi3kinase. Moreover, the study of a case of irak4 deficiency revealed, on neutrophil, a TLR9 pathway independent of irak4 and but dependent of pi3k.TOURS-BU Médecine (372612103) / SudocSudocFranceF

Responsabilités des parfums dans les allergies aux cosmétiques

TOURS-BU Sciences Pharmacie (372612104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Les complications infectieuses liées à l’utilisation des anticorps monoclonaux chez l’homme

Les anticorps monoclonaux (Acm) sont utilisés en pratique médicale courante dans le traitement de nombreuses maladies hématologiques ou inflammatoires. Il est indispensable d’en connaître le rapport bénéfice-risque avant d’utiliser ces traitements. En effet, ils peuvent être à l’origine d’infections, plus ou moins sévères selon la molécule et le protocole utilisés. Leurs cibles moléculaires précises, souvent exprimées par des cellules du système hématopoïétique ou immunitaire, expliquent qu’ils puissent induire, directement ou indirectement, une immunosuppression favorable au développement d’infections opportunistes, ou des réactions allergiques. Des infections graves ont été rapportées, nécessitant une prophylaxie anti-infectieuse et rappelant la nécessité d’une évaluation des risques avant l’instauration du traitement et d’une surveillance rigoureuse par la pharmacovigilance lors du suivi de ces nouvelles thérapeutiques