IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Developpement du ganglion stato-acoustique et de l'innvervation des recepteurs cochleaires chez le rat. Etude immunohistochimique des proteines du cytosquelette neuronal

SIGLEINIST T 72776 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Recherche de molécules impliquées dans l'inhibition de la régénération axonale dans le colliculus inférieur

Des cultures organotypiques de colliculus inférieur (CI) prélevées sur des animaux âgés de 6 jours (P6) sont capables de régénérer leurs axones commissuraux après lésion. Les mêmes axones sont incapables de traverser le site de lésion si le CI est prélevé sur des animaux au stade P10. L'objectif de ce travail de thèse était d'identifier des molécules pouvant participer à l'inhibition de la régénération axonale dans le CI au stade P10. Dans ce but, des banques enrichies en molécules du stade P6 ou du stade P10 ont été construites par hybridation soustractive suppressive. Après criblage par dot-bot, six clones ont été sélectionnés. Quatre clones du stade P10 correspondaient à des molécules connues : la neuroleukine (NLK), la calmoduline, Rho7/Rnd2 et la cortactine. Deux autres étaient de fonction inconnue : A11 et SSTM (short seven transmembrane protein). L'étude de la localisation des messagers de ces molécules par hybridation in situ révélé une expression préférentiellement neuronale dans le cerveau. De plus, leur niveau d'expression augmente dans le cerveau au cours du développement post-natal. Par immunohistochimie, des profils différents sont obtenus. La NLK est observée dans les soma neuronaux et dans les axones. La calmoduline est présente dans le corps cellulaire des neurones et dans les dendrites. Rho7/Rhd2 est détecté dans les axones et les cellules gliales de Bergmann du cervelet. La cortactine se localise au niveau de la région juxta-membranaire intracellulaire du soma des neurones et des dendrites. A11 et SSTM sont observés dans les neurones au niveau de la membrane cytoplasmique somatique et dendritique, où elles se localisent dans les contacts post-synaptiques, ainsi que dans les prolongements gliaux. Après une lésion du cortex cérébral, la NLK, la cortactine, A11 et SSTM sont surexprimés par les astrocytes réactifs. La NLK est en plus observée dans les axones lésés. La calmoduline et le Rho7/Rhd2 ne semblent pas être surexprimés après lésion. L'ensemble de ces travaux apporte de nouvelles données sur l'expression cérébrale des six molécules étudiées et suggère l'implication de certaines d'entre elles dans le processus de régénération axonale dans le système nerveux central.Sectionned commissural axons of inferior colliculus (IC) organotypique cultures from 6-day old animals (P6) are able to regenerate. In similar conditions, injured axons of IC from P10 are unable to cross through the lesion site. The purpose of this thesis work was to identify molecules potentially involved in the inhibition of axonal regeneration observed in the IC by P10. In this aim, suppression substractive hybridization was used to construct libraries enriched in P6 and P10 molecules. After a dot-blot screening, six clon,es were selected. Four of them, from P10 library, were known molecules, i.e. neuroleukin (NLK), calmodulin, Rho7/Rnd2 and cortactin. Two others were of unknown function i.e. A11 and SSTM (short seven transmembrane protein). In situ hybridization experiments have revealed that these molecule messengers are preferentially expressed by neurons in the brain. In addition, their level of expression increases in the brain during post-natal development. Immunohistochemistry showsdifferent patterns of distribution. NLK is observed in axons and neuronal somata. Calmodulin is present in the cell body and dendrites of neurons. Rho7/Rnd2 is detected in axons and in the cerebellar Bergmann glial cells. Cortactin is localized at the intracellular juxta-membrane level in the neuronal somata and dendrites. A11 and SSTM are present both at the cell body plasma membrane level and in dendrites, where they are localized in post-synaptic contacts, and in glial processes. After a mechanical trauma in the cerebral cortex region, NLK, cortactin, A11 and SSTM are overexpressed by reactive astrocytes. Moreover, NLK is observed in the regenerating axons. Calmodulin and Rho7/Rnd2 were not found to be overexpressed after the injury.All these works expend the knowledge of the cerebral expression of the six studied molecules and suggest the implication of some of them in the axonal regeneration process in the central nervous system.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Etude des mécanismes et des circuits neuronaux impliqués dans la douleur neuropathique trigéminale post-traumatique

CLERMONT FD-BCIU Odontol. (631132226) / SudocCLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

PKCγ-positive neurons gate light tactile inputs to pain pathway through pERK1/2 neuronal network in trigeminal neuropathic pain model

© 2015 by Quintessence Publishing Co Inc. Aims: To explore the possible relationship between protein kinase C gamma (PKCγ) and phosphorylated forms of extracellular signal-regulated kinases 1/2 (pERK1/2) in the rat medullary dorsal horn and the facial hypersensitivity indicative of dynamic mechanical allodynia (DMA) following chronic constriction of the infraorbital nerve (CCI-IoN). Methods: A well-established rat model of trigeminal neuropathic pain involving CCI-IoN was used. Facial mechanical hypersensitivity was tested with non-noxious dynamic mechanical stimulation (air-puff), and the medullary dorsal horn was examined immunohistochemically using PKCγ and pERK1/2 as pain markers. Statistical analysis was performed using Student t test or one-way analysis of variance (ANOVA). Results: Increased PKCγ and pERK1/2 expressions within the medullary dorsal horn were associated with DMA following CCI-IoN. A segmental network composed of PKCγ-positive cells located in medullary dorsal hor

Etude de protéines impliquées dans l'inhibition de la régénération axonale du système nerveux central, Nogo-A, NgR, Lingo-1 et de leur voie d'action intracellulaire (les Rho-GTPases Rho-A et Rac1)

A l'opposé du système nerveux central (SNC) immature, les axones du SNC adulte ne régénèrent pas après une lésion. La section des fibres commissurales du colliculus inférieur (CI) en culture organotypique est suivie d'une régénération axonale robuste au stade post-natal P6, mais d'une régénération déficiente à P12. Ce travail montre les expressions de la molécule inhibitrice Nogo-A, de son récepteur NgR, du partenaire Lingo-1 et des Rho-GTPases Rho-A et Rac1. Rgo-A inhibe l'extension de l'axone tandis que Rac1 la favorise. Ces molécules sont présentes dans les neurones, les fibres nerveuses et les cellules gliales de structures auditives (noyau cochléaire, complexe de l'olive supérieure et CI) aux stades étudiés P0, P6, P12 et adulte. Rho-A augmente entre P6 et P12, tandis que Rac1 diminue. Enfin, l'inhibition de Rho-A accroît la régénération des fibres commissurales lésées. Ces résultats suggèrent une implication des Rho-GTPases dans l'absence de régénération axonale du CI à P12.Unlike the immature central nervous system (CNS), the adult mammalian CNS is unable to regenerate axons following injury. Sectioning the inferior colliculus (IC) commissure in gerbil organotypic cultures at postnatal day P6 is followed by extensive axonal regeneration. By contrast, commissural axons sectioned at P12 fail to regenerate through the lesion site. The present study characterize the expression of proteins implicated in axonal regeneration failure. The immunohistochemical techniques show that Nogo-A, NgR, Lingo-1, and the Rho-GTPases Rho-A and Rac1 are widely expressed at P0, P6, P12 and adult stages in gerbil auditory structures (cochlear nucleus, superior olive and IC). Moreover, the western-blot technique reveal an increase in Rho-A expression between P6 and P12, and a decrease in Rac1. Finally, inhibition of Rho-A effector increase sectioned commissural fibers regeneration. TThese results suggest that Rho-GTPases are implicated in IC axonal regeneration failure at P12.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Electrical Synapses are Involved in Orofacial Neuropathic Pain

International audienc

Acute Tramadol Administration Induces the Expression of pERK1/2 in Different Limbic and Pain Processing Structures

International audienceTramadol is a painkiller with some abuse potentials. The current study aimed to investigate rat cerebral structures that were activated by acute intraperitoneal administration of tramadol (10 mg/kg). The expression of pERK1/2 was used as a molecular tool for tramadol-induced

mGlu5 receptor antagonist blocks bromocriptine-induced conditioned place preference in bilateral mesolimbic-lesioned rat

International audienceDopamine dysregulation syndrome (DDS) has been attributed to both dopamine replacement therapies (DRT) and the mesencephalic dopaminergic lesion. The DRT reinforcement effect is due to its action on the reward system, particularly on the nucleus accumbens (NAc). This nucleus receives two major projections, a glutamatergic from the prefrontal cortex and a dopaminergic from the posterior ventral tegmental area (pVTA). The latter modulate the former within the NAc. pVTA has been demonstrated to be implicated in the motivational effect of bromocriptine (dopamine 2 receptor (D2R) agonist) in bilat- eral pVTA-lesioned animals. Therefore the potential implication of the metabotropic glutamate receptor 5 (mGluR5) antagonist (MTEP: 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine) on bromocriptine-induced conditioned place preference (CPP) was explored. Results showed that the administration of the MTEP blocked completely the bromocriptine-induced CPP in bilateral pVTA-lesioned rats. Both the CPP acqui- sition and expression were abolished. These effects are due, at least to an increase of the glutamate concentration and that of mGlu5 receptor expression in the NAc shell of the pVTA-lesioned animals. Altogether these data demonstrated the importance of the mGlu5 receptor in the bromocriptine induced- reinforcement and that DDS is probably due to DRT effect on this glutamate receptor