Divergent Changes in the Sensitivity of Maturing T Cells to Structurally Related Ligands Underlies Formation of a Useful T Cell Repertoire

AbstractCD4+CD8+ thymocyte differentiation requires TCR signaling induced by self-peptide/MHC ligands. Nevertheless, the resulting mature T cells are not activated by these self-complexes, whereas foreign ligands can be potent stimuli. Here, we show that the signaling properties of TCR change during thymocyte maturation, differentially affecting responses to related peptide/MHC molecule complexes and contributing to this discrimination. Weak agonists for CD4+CD8+ thymocytes lose potency during development, accompanied by a change in TCR-associated phosphorylation from an agonist to a partial agonist/antagonist pattern. In contrast, sensitivity to strong agonists is maintained, along with full signaling. This yields a mature T cell pool highly responsive to foreign antigen while possessing a wide margin of safety against activation by self-ligands

Evolution of the mammalian lysozyme gene family

<p>Abstract</p> <p>Background</p> <p>Lysozyme <it>c </it>(chicken-type lysozyme) has an important role in host defense, and has been extensively studied as a model in molecular biology, enzymology, protein chemistry, and crystallography. Traditionally, lysozyme <it>c </it>has been considered to be part of a small family that includes genes for two other proteins, lactalbumin, which is found only in mammals, and calcium-binding lysozyme, which is found in only a few species of birds and mammals. More recently, additional testes-expressed members of this family have been identified in human and mouse, suggesting that the mammalian lysozyme gene family is larger than previously known.</p> <p>Results</p> <p>Here we characterize the extent and diversity of the lysozyme gene family in the genomes of phylogenetically diverse mammals, and show that this family contains at least eight different genes that likely duplicated prior to the diversification of extant mammals. These duplicated genes have largely been maintained, both in intron-exon structure and in genomic context, throughout mammalian evolution.</p> <p>Conclusions</p> <p>The mammalian lysozyme gene family is much larger than previously appreciated and consists of at least eight distinct genes scattered around the genome. Since the lysozyme <it>c </it>and lactalbumin proteins have acquired very different functions during evolution, it is likely that many of the other members of the lysozyme-like family will also have diverse and unexpected biological properties.</p

Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates

La recherche d'anticorps circulants par Elisa peut-elle remplacer l'immunofluorescence indirecte dans le diagnostic biologique des dermatoses bulleuses auto-immunes ? (étude des tests ELISA anti-desmogléine 1, -desmogléine 3 et -BP180 et de trois substrats en immunofluorescence indirecte dans 48 pemphigus, 57 pemphigoïdes bulleuses et 18 pemphigoïdes de la grossesse)

PARIS-BIUP (751062107) / SudocSudocFranceF

RECHERCHE DU DEFAUT MOLECULAIRE DANS DEUX LEUCODYSTROPHIES D'ETIOLOGIE INDETERMINEE (LE SYNDROME CACH ET LA MALADIE D'ALEXANDER)

CE TRAVAIL AVAIT POUR BUT D'IDENTIFIER LE DEFAUT MOLECULAIRE DE DEUX LEUCODYSTROPHIES D'ORIGINE INDETERMINEE : LE SYNDROME CACH (VANISHING WHITE MATER SYNDROME) ET LA MALADIE D'ALEXANDER. LE SYNDROME CACH EST UNE LEUCODYSTROPHIE IDENTIFIEE RECEMMENT SUR DES CRITERES CLINICO-RADIOLOGIQUES, DE TRANSMISSION AUTOSOMIQUE RECESSIVE. NOUS AVONS DECRIT LES LESIONS NEUROPATHOLOGIQUES DU SYNDROME CACH. IL S'AGIT D'UNE LEUCODYSTROPHIE CAVITAIRE, ORTHOCHROMATIQUE AVEC UNE AUGMENTATION DE LA DENSITE DES OLIGODENDROCYTES ET LA PRESENCE D'OLIGODENDROCYTES SPUMEUX. L'ORIGINALITE DE CES LESIONS EST VENUE RENFORCER L'EXISTENCE DE CETTE NOUVELLE ENTITE. L'ETUDE BIOCHIMIQUE A MONTRE UNE DIMINUTION GLOBALE DES CONSTITUANTS MYELINIQUES (LIPIDES ET PROTEINES), SANS ANOMALIE SPECIFIQUE. LE RECUEIL DE 27 FAMILLES DONT 12 MULTIPLEX A PERMIS DE DEMARRER UNE ETUDE DE LIAISON GENETIQUE. NOUS N'AVONS PAS MIS EN EVIDENCE DE LIAISON AVEC LE LOCUS 3Q27 PREALABLEMENT DECRIT, CE QUI SUGGERE UNE HETEROGENEITE GENETIQUE POUR LE SYNDROME CACH ET NOUS AVONS TROUVE UN LOCUS CANDIDAT SUR LE CHROMOSOME 7. LA MALADIE D'ALEXANDER, MAJORITAIREMENT SPORADIQUE, A ETE CARACTERISEE DES 1949 SUR DES CRITERES NEUROPATHOLOGIQUES : PROLIFERATION ASTROCYTAIRE, PRESENCE DIFFUSE DE FIBRES DE ROSENTHAL (INCLUSIONS ASTROCYTAIRES), ATTEINTE MYELINIQUE. LA DECOUVERTE DE FIBRES DE ROSENTHAL DANS LE SNC DE SOURIS TRANSGENIQUES SUREXPRIMANT LA GFAP, A FAIT DE CE GENE UN BON CANDIDAT. DES MUTATIONS DANS LA SEQUENCE CODANTE DU GENE GFAP ONT ETE IDENTIFIEES CHEZ 27 PATIENTS. DANS TOUS LES CAS IL S'AGIT DE MUTATIONS FAUX-SENS, HETEROZYGOTES, SURVENANT DE NOVO. LE GENE DE LA GFAP PARAIT DONC MAJORITAIREMENT IMPLIQUE DANS LA MALADIE D'ALEXANDER, MAIS L'ABSENCE DE MUTATION DANS LA SEQUENCE CODANTE DE DEUX CAS IMPOSE DE CONTINUER L'ETUDE DE CE GENE ET NE PERMET PAS D'ELIMINER L'IMPLICATION D'AUTRES GENES. CETTE DECOUVERTE VIENT ENRICHIR LA LISTE DES PATHOLOGIES LIEES AUX FILAMENTS INTERMEDIAIRES ET A PERMIS DE DECRIRE LA PREMIERE MALADIE PRIMITIVEMENT ASTROCYTAIRE, NON TUMORALE.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Three genes, four demyelinating neuropathies: First genotype/phenotype correlations | Trois genes et quatre neuropathies peripheriques myelinques: Premieres correlations genotype/phenotype

In most vertebrates, axons are usually ensheathed by myelin, a multi-lamellar structure that ensures the fidelity of nerve transmission and increases considerably nerve conduction velocity along the fibers. In the peripheral nervous system (PNS), myelin is formed by the extension of the plasma membrane of Schwann cells that wrap in spiral as many as 50 layers of double membrane structures around the axon. The myelin sheaths consist mostly of compact myelin that expresses a distinct set of structural proteins, namely myelin protein zero (P0), which is the most abundant component, peripheral myelin protein 22 (PMP22) and myelin basic protein. PNS compact myelin is interrupted by regions filled with cytoplasm, the incisures of Schmidt-Lanterman. These and the paranodal regions of Schwann cells express a distinct set of proteins that include myelin-associated glycoprotein and connexin32 (Cx32). It has now been demonstrated that genetic abnormalities in the genes encoding PMP22, P0 and Cx32, are responsible for the vast majority of demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth disease type 1, X-linked Charcot-Marie-Tooth, Dejerine-Sottas syndrome, hereditary neuropathy with liability to pressure palsies and congenital hypomyelination. PMP22 is an integral membrane protein whose function is still poorly understood. P0 is a cell adhesion protein that contributes a sort of adhesive tape that holds together the extracellular leaflets of compact myelin. Cx32 is a channel-forming protein that is thought to provide the basis for a radial diffusional pathway of signaling molecules and metabolites across the myelin layers. Recent studies on the molecular structure and cell biology of these three pivotal proteins for myelin homeostasis have begun to shed light on some of the pathophysiological mechanisms that are specific to each syndrome.link_to_subscribed_fulltex

Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their ability to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four others were able to generate intercellular currents of the same order of magnitude as those induced by wild-type Cx32 (Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that exhibited changes in the sensitivity and kinetics of voltage dependence with respect to that of Cx32wt. The four mutations were also capable of interacting in heterotypic configuration with the wild-type protein, and in one case the result was