Modulation of HLA-G and HLA-E expression in human neuronal cells after rabies virus or herpes virus simplex type 1 infections

Human Leukocyte Antigen (HLA)-G and E are nonclassical human MHC class I molecules. They may promote tolerance leading to virus and tumor immune escape. We recently described that the herpes simplex virus type 1 (HSV-1), a neurotropic virus inducing chronic infection and neuron latency, and rabies virus (RABV), a neuronotropic virus triggering acute neuron infection, up-regulate HLA-G expression in human neurons (NT2-N). Surface expression was only detected after RABV infection. We investigated here whether RABV and HSV-1 up-regulate HLA-E expression in human neuronal precursors (Ntera-2D/1). We found that RABV, not HSV-1, up-regulates HLA-E expression, nevertheless HLA-E could not be detected on the surface of RABV-infected Ntera-2D/1. Altogether these data suggest that HLA-G and not HLA-E could contribute to the immune escape of RABV. In contrast, there was no evidence that these molecules are used by latent HSV-1 infection. Thus, neurotropic viruses that escape the host immune response totally (RABV) or partially (HSV-1) regulate HLA-G expression on human neuronal cells differentially.     

Relative stability of alexithymia and openness to emotions in one psychiatric day hospital setting

Alexithymia (literally, difficulty finding words for emotions) and openness to emotions (OE: referring to the cognitive representation, communication, regulation, perception of internal and external bodily sensations, and social restriction of emotions) are strongly linked to psychopathology. The absolute and relative stability hypotheses were tested in order to determine whether significant changes occurred on these constructs after therapy, a condition where changes were expected for both constructs. Negative attitudes toward treatment (NTI) and perceived social support (PSS) were expected to significantly predict alexithymia and OE. Patients (N = 179) who participated in this longitudinal study filled in the Toronto Alexithymia Scale, the Dimensions of Openness to Emotions Scale, the NTI subscale, the Multidimensional Scale of Perceived Social Support, and the Social Desirability Scale. After treatment, we observed significant decrease of all alexithymia scores and significant increases of three OE scores, that is, cognitive representation, communication, and regulation of emotions. Regression analyses revealed that gender, age, NTI, and PSS were significant predictors of alexithymia and OE. NTI strongly predicted lower OE levels and higher alexithymia levels, whereas PSS had opposite predicting effects on these constructs. In conclusion, the significant changes, and the moderate to high correlational levels observed between before and after alexithymia and OE scores, strengthen the relative stability hypothesis for both constructs. In addition, PSS represents a protective factor and NTI a vulnerability indicator for therapists. Our aim is to optimize treatment by providing therapists treating emotion difficulties a more concrete array of variables that potentially either promote or subvert recovery.     

Protein kinase C isotypes required for phorbol-ester induction of stromelysin-1 in rat fibroblasts

The phorbol-ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent inducer of the metalloproteinase stromelysin in fibroblasts in vivo and in several cultured cell lines. Rat-1 and Rat-2 fibroblasts, however, do not respond to TPA stimulation by induction of stromelysin gene activity, although collagenase promoter-mediated activity is induced threefold by TPA treatment in these cells. We determined that rat fibroblasts expressed protein kinase C (PKC) α, PKCδ, PKCϵ, and PKCζ but neither the mRNA nor the protein for PKCβ. When Rat-2 fibroblasts were stably transfected with an expression vector producing PKCβ, however, TPA treatment of these variants resulted in a 3.1-fold induction of stromelysin promoter-mediated luciferase activity compared with a 1.3-fold induction in parental Rat-2 cells (P < 0.002). Transient transfection of PKCϵ produced a small but significant increase in TPA-stimulation of both stromelysin- and collagenase-mediated gene expression. These results suggest that there are PKC isotype-specific signaling pathways that can differentially regulate matrix metalloproteinase gene expression. © 1996 Wiley-Liss, Inc.     

Redirecting the complete T cell receptor/CD3 signaling machinery towards native antigen via modified T cell receptor

We show that a chimeric T cell receptor (TCR) β chain consisting of a single-chain Fv portion derived from a monoclonal antibody and the full TCR β chain is able to assemble functionally with endogenous TCR/CD3 components and transfer the antibody specificity as well as the TCR specificity into TCRβ⁻ as well as into TCRβ⁺ T cells. This allows the incorporation new non-major histocompatibility complex-restricted ligand specificities into the intact TCR/CD3 complex which can exploit the full range of biological activities of the endogenous TCR signaling machinery. This approach can provide wider opportunities to redirect T cells to virus or tumor antigen-bearing cells.     

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.     

Analysis of the skin of mice humanized for the immune system

Development of new immunotherapeutic strategies relies on the ability to activate the right cells at the right place and at the right moment and on the capacity of these cells to home to the right organ(s). Skin delivery has shown high potency for immunotherapeutic administration. However, an adequate in vivo model of human skin immunity is still a critical bottleneck. We demonstrated here that the skin of human immune system mice is colonized by human hematopoietic cells, mainly human T cells and that complementation with human antigen‐presenting cells at the vaccination site allowed the induction of an immune response.