Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID

We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3–9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30 mg/m2 per day) from day −7 to day −2 (total dose 180 mg/m2) and BU 4 mg/kg per day from day −3 to day −2 (total dose 8 mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21–77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID

Effects of A- and B-site (co-)acceptor doping on the structure and proton conductivity of LaNbO4

B-site and A- and B-site co-doped lanthanum niobates, La(1-x)DA(x)Nb(1-y)DB(y)O(4-delta), where D-A stands for Ca or Ba and D-B for Ga, Ge or In (x = 0 or 0.01; y = 0.01), have been synthesized via the solid-state route. Essentially single-phase materials were obtained after 10 h at 1500 degrees C with monoclinic Fergusonite structure at room temperature. The unit cell volume increases slightly with the presence of the acceptor. The electrical conductivity of the materials, characterized as a function of the temperature from 300 degrees C to 900 degrees C under wet reducing conditions with AC impedance spectroscopy, was dominated by protons. The maximum conductivity of 4.1 . 10(-4) S . cm(-1) at 900 degrees C was obtained for La0.99Ca0.01Nb0.99Ga0.01O4-delta, which is a factor of similar to 2.5 lower than the highest conductivity reported for the A-site Ca-doped LaNbO4. Based on a semi-quantitative evaluation it was shown that the hydration of the B-site and A- and B-site co-doped LaNbO4, is slightly more exothermic and that the proton mobility has higher activation enthalpies than Ca-doped LaNbO4. This is accounted for by a stronger association between the acceptor and the proton for B-site than for A-site doping. (c) 2011 Elsevier B.V. All rights reserved

Natural killer cell-mediated lysis of T cell lines chronically infected with HIV-1.

The susceptibility of HIV-1-infected CD4+ T cell lines to natural killer (NK) cell-mediated lysis was examined. Non-adherent peripheral blood mononuclear cells (PBMC) of healthy adults lysed HUT cells chronically infected with the IIIB or WMJ1 strains of HIV-1 to a significantly greater extent than uninfected HUT cells. In contrast, Sup-T1 cells chronically infected with these two strains of HIV-1 were not lysed to a greater extent than uninfected Sup-T1 cells. Clone A1.25-infected Sup-T1 (A1.25/Sup-T1), derived from IIIB-infected Sup-T1 cells (IIIB/Sup-T1), were susceptible to non-adherent PBMC-mediated lysis, as were A1.25-infected HUT cells (A1.25/HUT). When non-adherent PBMC were depleted of CD16 (Leu-11b)+ NK cells by treatment with anti-Leu-11b plus C, lysis of HIV-1-infected HUT or Sup-T1 cells was reduced to low levels, indicating that the lysis was mediated by NK cells. Expression of HIV antigens on these target cells did not correlate with their susceptibility to NK cell-mediated lysis. Depletion of interferon-alpha (IFN-alpha) producing HLA-DR+ cells from non-adherent PBMC had no effect on the magnitude of NK cell-mediated lysis of IIIB or WMJ1-infected HUT cells. In contrast, lysis of A1.25/Sup-T1 or A1.25/HUT cells required the presence of HLA-DR+ cells. IFN-alpha production appeared to be required for NK cell-mediated lysis of A1.25/Sup-T1 or A1.25/HUT cells, while lysis of HUT cells infected with the WMJ1 or IIIB strains of HIV-1 was IFN-alpha independent. These results indicate considerable variability in the susceptibility of different HIV-1 infected T cell lines to NK cell-mediated lysis and suggest the existence of alternative mechanisms of activation of NK cells for lysis of HIV-1-infected T cell lines

Gestion des forêts protectrices dans les Alpes - un aperçu

International audienceMany mountain forests in the Alps protect residential areas and infrastructures from natural hazards. They are described as protection forests and their management aims to permanently provide a high protective effect. The maintenance and management of these forests are continuously improved and have reached a high standard. There is now a better understanding of the protective effects of the forest against natural hazards. In the Alps, there are currently several projects being conducted which aim to harmonize the assessment of natural hazards, damage potential and a resulting classification of protection forests. It is the objective to apply funding where needed in order to prevent damage from natural hazards. Currently, there is a need for improvement in the area of monitoring with advanced technology, such as Laser-Scanning (LIDAR), in linking inventory data from different sources, in simulation modeling to better estimate the long-term benefit of measures in the protection forest, and in transboundary collaboration.Dans les Alpes, de nombreuses forêts protègent des localités et des infrastructures contre les dangers naturels. Elles sont désignées comme forêts protectrices. Elles sont soignées de façon à offrir durablement un effet protecteur aussi grand que possible. L'entretien et la gestion de ces forêts sont constammment améliorés et on atteint un niveau élevé. L'effet de la forêt contre les dangers naturels est de mieux en mieux connu. Plusieurs projets sont en cours dans l'arc alpin en vue d'harmoniser l'appréciation des dangers naturels et des dommages potentiels, et, à partir de là, la délimitation des forêts protectrices. L'objectif est d'utiliser les moyens disponibles pour la prévention des dangers de manière plus ciblée. Les possibilités d'amélioration se situent dans le suivi au moyen de techniques modernes (laser-scanning LIDAR), dans la liaison avec des données d'inventaire provenant de différentes sources, dans les modèles de simulation permettant de mieux évaluer l'efficacité à long terme des mesures en forêt protectrice, ainis que dans les collaborations transfontalières

A Compact Manufacturable 76–77-GHz Radar Module for Commercial ACC Applications

The design and measured results of a single-substrate transceiver module suitable for 76-77-GHz pulsed-Doppler radar applications are presented. Emphasis on ease of manufacture and cost reduction of commercial millimeter-wave systems is employed throughout as a design parameter. The importance of using predictive modeling techniques in understanding the robustness of the circuit design is stressed. Manufacturing techniques that conform to standard high-volume assembly constraints have been used. The packaged transceiver module, including three waveguide ports and intermediate-frequency output, measures 20 mm x 22 mm x 8 mm. The circuit is implemented using discrete GaAs/AlGaAs pseudomorphic high electron mobility transistors (pHEMTs), GaAs Schottky diodes, and varactor diodes, as well as GaAs p-i-n and pHEMT monolithic microwave integrated circuits mounted on a low-cost 127-mum- thick glass substrate, A novel microstrip-to-waveguide transition is described to transform the planar microstrip signal into the waveguide launch. The module is integrated with a quasi-optical antenna. The measured performance of both the component parts and the complete radar transceiver module is described

Schutzwaldmanagement in den Alpen - eine cbersicht

Many mountain forests in the Alps protect residential areas and infrastructures from natural hazards. They are described as protection forests and their management aims to permanently provide a high protective effect. The maintenance and management of these forests are continuously improved and have reached a high standard. There is now a better understanding of the protective effects of the forest against natural hazards. In the Alps, there are currently several projects being conducted which aim to harmonize the assessment of natural hazards, damage potential and a resulting classification of protection forests. It is the objective to apply funding where needed in order to prevent damage from natural hazards. Currently, there is a need for improvement in the area of monitoring with advanced technology, such as Laser-Scanning (LIDAR), in linking inventory data from different sources, in simulation modeling to better estimate the long-term benefit of measures in the protection forest, and in transboundary collaboration