T-dependent B cell activation and differentiation in Lat Y136F mice : polyclonal response leading to autoimmune disease

SUMMARY LatY136F knock-in mice harbor a point mutation in tyrosine 136 of the linker for activation of T cells (LAT), and show accumulation of TH2 effector cells leading to IgG1 and IgE hypergammaglobulinemia. The observed polyclonal. B cell activation was not a direct effect of the mutation on B cells since in the absence of T cells mutant B cells did not show an activated phenotype. After adoptive transfer of LAT mutant T cells into wild type (WT) Tcell-deficient recipients, recipient B cells became activated. We show in vivo and in vitro that the LatY136F mutation promotes Tcell-dependent B cell activation leading to germinal center, memory and plasma cell formation even in the absence of MHC class II. This effect was, however, dependant on CD40 and CD80/CD86. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses were found. Characterization of the abundant plasmablasts observed in. secondary lymphoid organs of LatY136F mice revealed the presence of a previously uncharacterized CD93expressing subpopulation, whose existence was confirmed in WT mice after immunization. In LatY136F mice, B cell activation was polyclonal and not antigen-driven, since the increase in serum IgG1 and IgE concentrations involved antibodies and autoantibodies with different specificities equally. Although the non-complement-fixing IgG1 and IgE were the only isotypes significantly increased in LatY136F serum, we observed early onset of systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that TH2 cells developing in LatY136F mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease. RESUME Les souris présentent une mutation ponctuelle au niveau de la tyrosine 136 de l'adaptateur requis pour l'activation des cellules T (LAT) et développent, de ce fait, une accumulation de cellules T effectrices de type TH2 ainsi qu'une hypergammaglobulémie des isotypes IgG1 et IgE. Dans ce modèle murin, l'activation des cellules B et la production d'anticorps qui y est associée ne sont pas dues à un effet direct de la mutation. Nous avons mis en évidence que l'interaction physique entre cellules T activées et cellules B est indispensable au développement de ce phenotype. D'un point de vue moléculaire, cette interaction ne requiert pas l'intervention des complexes majeurs d'histocompatibilité de classe II, garant de la spécificité d'une réponse immunitaire. Cependant, les molécules de costimulation CD40 et CD80/CD86 sont indispensables à une réponse complète des cellules B. Les souris LatY136F développent d'importantes populations de cellules B des centres germinatifs, de cellules B mémoires ainsi que de cellules sécrétant des anticorps, qui présentent les mêmes caractéristiques que lors d'une réponse immunitaire à un antigène classique. En observant plus précisément les plasmablastes présents dans les ganglions des souris LatY13sF, nous avons détecté une sous-population exprimant CD93; l'expression de ce marqueur par les cellules B n'a jamais été mise en évidence durant une réponse immunitaire. Cependant, notre étude a permis de confirmer sa présence, dans les ganglions de souris de type sauvage, lors d'immunisation avec différents antigènes. Nous avons montré que l'activation des cellules B des souris LatY136F est polyclonale et n'est pas dirigée par un antigène; les taux d'autoanticorps augmentent de manière proportionnelle à ceux des anticorps totaux. Bien que les IgG1 et les IgE ne soient pas des isotypes connus pour leurs propriétés pathogéniques, nous avons observé le développement d'une autoimmunité systémique caractérisée par une néphrite impliquant des dépôts d'autoanticorps du type IgE ainsi que par une sévère proteinurée.

Degeneracy of antigen recognition as the molecular basis for the high frequency of naive A2/Melan-a peptide multimer(+) CD8(+) T cells in humans.

In contrast with the low frequency of most single epitope reactive T cells in the preimmune repertoire, up to 1 of 1,000 naive CD8(+) T cells from A2(+) individuals specifically bind fluorescent A2/peptide multimers incorporating the A27L analogue of the immunodominant 26-35 peptide from the melanocyte differentiation and melanoma associated antigen Melan-A. This represents the only naive antigen-specific T cell repertoire accessible to direct analysis in humans up to date. To get insight into the molecular basis for the selection and maintenance of such an abundant repertoire, we analyzed the functional diversity of T cells composing this repertoire ex vivo at the clonal level. Surprisingly, we found a significant proportion of multimer(+) clonotypes that failed to recognize both Melan-A analogue and parental peptides in a functional assay but efficiently recognized peptides from proteins of self- or pathogen origin selected for their potential functional cross-reactivity with Melan-A. Consistent with these data, multimers incorporating some of the most frequently recognized peptides specifically stained a proportion of naive CD8(+) T cells similar to that observed with Melan-A multimers. Altogether these results indicate that the high frequency of Melan-A multimer(+) T cells can be explained by the existence of largely cross-reactive subsets of naive CD8(+) T cells displaying multiple specificities.

The Europeanisation of the measurement of diversity in education: a soft instrument of public policy

Faced with an increasing number of data and rankings, the author questions the roles of the different groups of actors who were originally involved in questioning the use of statistical indicators as a means of addressing issues of access to higher education. The comparison and nature of these international (UNESCO, OECD, EUROSTAT) and national (Germany, England, France, Switzerland) indicators in matters of inequalities of access to higher education question the tension between the discourses and the indicators they generate, and their recording at the national level. Who says what and with what consequences? What range of actors are involved in this process? What kind of power relations forms them? The author discusses how the issue of inequalities of access to higher education got on to the agendas of European organisations, identifies the policies that were defined, and sets them against an array of indicators, showing the discrepancy between the discourses and what the indicators reveal, the gap between the recommendations and the available tools. Why is there such a contrast? What are the mechanisms at work? Is it a technical or a political problem? What does this discrepancy reveal as far as national specificities within the construction of social inequalities are concerned?

Anti-HLA antibody repertoire after IVIg infusion in highly sensitized patients waiting for kidney transplantation.

Polyclonal intravenous immunoglobulin (IVIg) treatment reduces crossmatch positivity and increases rates of transplantation in highly sensitised patients (HS). We quantified the panel reactive antibody (PRA) by microlymphocytotoxicity (MLCC), and we analysed anti-HLA class I and class II IgG specific antibody repertoire by Luminex before and after IVIg infusion alone in HS patients awaiting kidney transplantation. Five patients received three monthly infusions of 1 g/kg of IVIg. Serum samples collected pre and post IVIg treatment were submitted for PRA analysis by MLCC. Anti-class I and anti-class II antibody specificities were then tested by Luminex. We focused on the anti-HLA class I and class II antibodies directed against HLA expressed by a previous graft. We also analysed the anti-HLA antibody repertoire in three patients who had not received IVIg infusion. The PRA level determined by MLCC decreased significantly in one of the five patients, dropping from 40% to 17%. The Luminex assay showed fluctuations of the anti-HLA antibody levels over time, but no significant longterm modifications of the anti-HLA antibody repertoire were observed, even in the patient with a strong and prolonged reduction of the PRA determined by MLCC. Our results show that IVIg at 1 g/kg is not sufficient to reduce PRA and does not modify the repertoire of specific anti-HLA antibody determined by Luminex.

El tractament arxivístic dels fons personals de científics

La primera part d’aquest treball està dedicada a la caracterització dels fons personals de científics, analitzant-los com a fons personals d’una banda i com a fons de ciència de l’altra. Des d’ambdues vessants identifiquem unes característiques pròpies que els singularitzen dins d’aquestes tipologies generals, posen de manifest la seva fragilitat i a la vegada justifiquen la necessitat d’un tractament arxivístic diferenciat. Advocant per una col•laboració activa entre arxivers i historiadors de la ciència, a la segona part es proposen unes pautes per al tractament integral d’aquests fons particulars, des de la primera gestió de l’ingrés fins a la seva difusió, tenint-ne en compte les especificitats, les peculiaritats del context de producció científica i les diverses casuístiques que es poden donar en un fons d’aquestes característiques. Paraules clau: fons personals de científics, tractament arxivístic, tractament integral de fons, arxius en història de la ciència

Characterisation of the putative effector interaction site of the regulatory HbpR protein from Pseudomonas azelaica by site-directed mutagenesis.

Bacterial transcription activators of the XylR/DmpR subfamily exert their expression control via σ(54)-dependent RNA polymerase upon stimulation by a chemical effector, typically an aromatic compound. Where the chemical effector interacts with the transcription regulator protein to achieve activation is still largely unknown. Here we focus on the HbpR protein from Pseudomonas azelaica, which is a member of the XylR/DmpR subfamily and responds to biaromatic effectors such as 2-hydroxybiphenyl. We use protein structure modeling to predict folding of the effector recognition domain of HbpR and molecular docking to identify the region where 2-hydroxybiphenyl may interact with HbpR. A large number of site-directed HbpR mutants of residues in- and outside the predicted interaction area was created and their potential to induce reporter gene expression in Escherichia coli from the cognate P(C) promoter upon activation with 2-hydroxybiphenyl was studied. Mutant proteins were purified to study their conformation. Critical residues for effector stimulation indeed grouped near the predicted area, some of which are conserved among XylR/DmpR subfamily members in spite of displaying different effector specificities. This suggests that they are important for the process of effector activation, but not necessarily for effector specificity recognition.

Psychopharmacology in supportive care of cancer: a review for the clinician. IV. Other psychotropic agents

Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for secondline treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents requires that both their specificities and the particular characteristics of palliative care patients are taken into account.

Transcriptional regulatory patterns of the myelin basic protein and malic enzyme genes by the thyroid hormone receptors alpha1 and beta1.

While there is evidence that the two ubiquitously expressed thyroid hormone (T3) receptors, TRalpha1 and TRbeta1, have distinct functional specificities, the mechanism by which they discriminate potential target genes remains largely unexplained. In this study, we demonstrate that the thyroid hormone response elements (TRE) from the malic enzyme and myelin basic protein genes (METRE and MBPTRE) respectively, are not functionally equivalent. The METRE, which is a direct repeat motif with a 4-base pair gap between the two half-site hexamers binds thyroid hormone receptor as a heterodimer with 9-cis-retinoic acid receptor (RXR) and mediates a high T3-dependent activation in response to TRalpha1 or TRbeta1 in NIH3T3 cells. In contrast, the MBPTRE, which consists of an inverted palindrome formed by two hexamers spaced by 6 base pairs, confers an efficient transactivation by TRbeta1 but a poor transactivation by TRalpha1. While both receptors form heterodimers with RXR on MBPTRE, the poor transactivation by TRalpha1 correlates also with its ability to bind efficiently as a monomer. This monomer, which is only observed with TRalpha1 bound to MBPTRE, interacts neither with N-CoR nor with SRC-1, explaining its functional inefficacy. However, in Xenopus oocytes, in which RXR proteins are not detectable, the transactivation mediated by TRalpha1 and TRbeta1 is equivalent and independent of a RXR supply, raising the question of the identity of the thyroid hormone receptor partner in these cells. Thus, in mammalian cells, the binding characteristics of TRalpha1 to MBPTRE (i.e. high monomer binding efficiency and low transactivation activity) might explain the particular pattern of T3 responsiveness of MBP gene expression during central nervous system development.

Creativity in Collaborative Learning across the Life Span

Peer-reviewed

Traitement des plagiocéphalies postérieures d'origine positionnelle [Treatment of posterior positional plagiocephaly]

In 1992, the American academy of paediatrics has recommended that infants be placed on their backs to sleep, because prone sleeping has been correlated with sudden infant death syndrome. Following this article, medical paediatric community has documented an exponential increase in the diagnosis of posterior cranial deformities, which were considered as the consequence of unrelieved pressure onto the occiput during infant sleep. These last 15 years, management of posterior positional plagiocephaly has evolved but is still not standardized; it varies according to local specificities, and medical or parental preferences. Treatment of deformational plagiocephaly includes preventive counseling, repositioning adjustments and exercises, physiotherapy, osteopathy, treatment by dynamic cranial orthosis. On extremely rare occasions, corrective surgery is proposed. This article aims at reviewing the epidemiologic, diagnostic, and various therapeutic options of posterior positional plagiocephaly.

Systems medicine and integrated care to combat chronic noncommunicable diseases

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

Les marquages corporels à l'adolescence : expression d'un mal-être profond? : se marquer pour se démarquer : du repérage des signes au choix des réponses adaptées

La problématique des marquages corporels en tant que pratiques ancestrales s'insèrent dans des formes contemporaines d'inscription corporelle. Nous nous sommes permis d'essayer de savoir s'il s'agissait toujours d'une expression d'un malaise psychologique important ? Quelles peuvent en être les conséquences ? Pourquoi marquer le corps ? La mise en oeuvre de ce travail s'est articulée en deux phases, au départ, nous avons opéré par une pré-enquête d'envergure qui a regroupé 200 adolescents (10 filles et 190 garçons). Ensuite et dans un deuxième temps nous avons interrogé dix adolescents qui se marquent la peau dont trois garçons, âgés de quinze à dix-neuf ans. Grâce à une « tri approche » : Entretien clinique, tests du Rorschach et du TAT. Les résultats auxquels nous sommes parvenus peuvent être résumés comme suit : ces pratiques expriment une souffrance qui peine à trouver une voie d'expression symbolique autre que le corps, l'angoisse et la relation d'objet du type anaclitique, l'organisation défensive renseigneraient essentiellement sur des défenses narcissiques, centrées notamment autour du clivage et le retournement sur soi, une identité fragile marquée par une image du corps et représentation de soi fragiles et un sur (dés) investissement des limites. Il s'agit d'une emprise sur le corps et sur les marques mêmes, permettant de retrouver l'objet et le recréer. À partir des principaux résultats obtenus, nous envisageons de travailler, en filigrane sur les spécificités des types de marquages corporels existant en Algérie. En effet si le présent travail s'est étayé sur une analyse prônant la globalité, un comparatif entre les types de marquages, de même, l'établissement d'un lien entre la symbolique de certaines pratiques et les soubassements psychodynamiques qui l'entourent, serait d'un apport considérable dans la compréhension du fait étudié dans ses moindres « recoins ». -- The problem of the physical markings as ancestral practices fit into contemporary forms of physical registration. We allowed to try to know if it was always about an expression of an important psychological illness? What can be the consequences? Why to mark the body? The application of this work articulated in two phases, at first, we operated by a large-scale pre- inquiry which grouped together 200 teenagers (10 girls and 190 boys). Then and in the second time we interrogated ten teenagers who mark the skin among which three boys, from fifteen to nineteen years old. Thanks to one « sorting approaches »: clinical Interview, tests of Rorschach and TAT. The results which we reached can be summarized as follows: these practices express a suffering which has difficulty in finding a way of symbolic expression other one than the body, the fear and the relation of object of the type anaclitique, the defensive organization would inform essentially about narcissistic defences, centred notably around the cleavage and the reversal on one, a fragile identity marked by an image of the body and the representation of one fragile and one on investment of the limits. It is about an influence on the body and on the marks, allowing to find the object and to recreate it. From the main obtained results, we intend to work, between the lines on the specificities of the types of physical markings existing in Algeria. Indeed if the present work supported on an analysis lauding the global nature, a comparative degree between the types of markings, also, the establishment of a link between the symbolism of certain practices and the bases psychodynamiques who surround him, would be of a considerable contribution in the understanding of the fact studied in its slightest « hidden recesses ».

Regional determinants of firm entry in a developing country

We analyse the determinants of firm entry in developing countries using Argentina as an illustrative case. Our main finding is that although most of the regional determinants used in previous studies analysing developed countries are also relevant here, there is a need for additional explanatory variables that proxy for the specificities of developing economies (e.g., poverty, informal economy and idle capacity).We also find evidence of a core-periphery pattern in the spatial structure of entry that seems to be mostly driven by differences in agglomeration economies. Since regional policies aiming to attract new firms are largely based on evidence from developed countries, our results raise doubts about the usefulness of such policies when applied to developing economies. JEL classification: R12, R30, C33. Key words: Firm entry, Argentina, count data models.

Systems Medicine and Integrated Care to Combat Chronic Noncommunicable Diseases.

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates.

To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.