Pascal Rihet

Bio: Pascal Rihet is an academic researcher from Aix-Marseille University. The author has contributed to research in topics: Plasmodium falciparum & Malaria. The author has an hindex of 26, co-authored 64 publications receiving 2548 citations. Previous affiliations of Pascal Rihet include French Institute of Health and Medical Research.

Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Abstract: The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.

Evidence for an association between human resistance to Schistosoma mansoni and high anti-larval IgE levels.

Abstract: The anti-larval IgE antibody response of adolescents with high or low resistance to infection by Schistosoma mansoni was evaluated before parasitological cure with oxamniquine and over an extended post-treatment period during which the least resistant subjects regained high infections. IgE from most sera, taken at several bleeding times before and after treatment, reacted, on immunoblots, with a large number of antigens (Ag) in schistosomular tegument extract. A family of 120-165-kDa cross-reacting molecules and a 85-kDa Ag were the most prominent Ag. Some of these determinants were shown to be located on the outer tegumental membrane and to be accessible to IgE on living larvae. The comparison of IgE between the two study groups showed that IgE levels were on average six-to eightfold higher (p less than 0.01) in the sera of the most resistant adolescents whereas there was no difference in patterns of Ag recognition between study groups. In contrast to IgE, anti-larval IgG and IgM levels were either similar in both groups or higher in the least resistant subjects when these exhibited high reinfection levels. IgG that competed for the binding of IgE to larval Ag were detected in most sera and their levels were higher in the least resistant group after reinfection. Finally, the treatment had no observable long-lasting effects on the levels and on the specificity of the anti-larval IgE. Altogether, these observations can be taken as evidence supporting a role of IgE in human resistance to infection by S. mansoni.

Resistance to Schistosoma mansoni in Humans: Influence of the IgE/IgG4 Balance and IgG2 in Immunity to Reinfection after Chemotherapy

Abstract: The hypothesis of an association between human resistance to reinfection by the parasite Schistosoma mansoni and anti-larval immunoglobulin isotypes was tested by logistic regression in the presence of the explicative variables water contact, age, and sex. Of the seven isotypes tested (IgM, IgG1, IgG2, IgG3, IgG4, IgA, and IgE), only IgE, IgG4, and IgG2 showed an association (positive for IgE and negative for IgG2 and IgG4) with resistance to reinfection after chemotherapy. The opposite effects of IgE and IgG4 were undissociable in the analysis, indicating that these isotypes probably antagonize each other in protection. The negative association of IgG2 with resistance is consistent with the view that anti-carbohydrate antibodies may facilitate reinfection. Finally, epidemiologic and immunologic studies support the view that there is a progressive but slow development of acquired immunity in children and adolescents.

High Immunoglobulin G2 (IgG2) and Low IgG4 Levels Are Associated with Human Resistance to Plasmodium falciparum Malaria

Abstract: There is accumulating evidence for a role of immunoglobulin G (IgG) in protection against malarial infection and disease. Only IgG1 and IgG3 are considered cytophilic and protective against P. falciparum, whereas IgG2 and IgG4 were thought to be neither and even to block protective mechanisms. However, no clear pattern of association between isotypes and protection has so far emerged. We analyzed the isotypic distribution of the IgG response to conserved epitopes and P. falciparum blood-stage extract in 283 malaria-exposed individuals whose occurrence of infection and malaria attack had been monitored for about 1 year. Logistic regression analyses showed that, at the end of the season of transmission, high levels of IgG2 to RESA and to MSP2 epitopes were associated with low risk of infection. Indeed, IgG2 is able to bind FcγRIIA in individuals possessing the H131 allele, and we showed that 70% of the study subjects had this allele. Also, high specific IgG4 levels were associated with an enhanced risk of infection and with a high risk of malaria attack. Moreover, specific IgG2 and IgG3 levels, as well as the IgG2/IgG4 and IgG3/IgG4 ratios, increased with the age of subjects, in parallel with the protection against infection and disease. IgG4 likely competes with cytophilic antibodies for antigen recognition and may therefore block cytotoxicity mediated by antibody-activated effector cells. In conclusion, these results favor a protective role of IgG3 and IgG2, which may activate effector cells through FcγRIIA, and provide evidence for a blocking role of IgG4 in malarial infection and disease.

Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33.

Abstract: Plasmodium falciparum malaria remains a major cause of morbidity and mortality in many tropical countries, especially those in sub-Saharan Africa. Human genetic control of malaria infection is poorly understood; in particular, genes controlling P. falciparum blood infection levels remain to be identified. We recently evidenced the existence of complex genetic factors controlling blood infection levels in an urban population living in Burkina Faso. We performed, on 153 sibs from 34 families, sib-pair linkage analyses between blood infection levels and chromosome 5q31-q33, which contains numerous candidate genes encoding immunological molecules. Our results, obtained by means of the two-point Haseman-Elston (HE) method and a nonparametric (NP) approach, show linkage of parasitemia to D5S393 (P=.002) and D5S658 (P=.0004). Multipoint analyses confirmed linkage, with a peak close to D5S658 (P=.0013 and P=.0007 with the HE and NP methods, respectively). The heritability of the locus was .48, according to the two-point results, and .43, according to the multipoint results; this indicates that its variation accounted for approximately 45% of the variance of blood infection levels and that the locus plays a central role in the control of parasitemia. The identification of the gene is, therefore, of major interest in understanding the mechanisms controlling P. falciparum parasitemia.

Integrative analysis of 111 reference human epigenomes

Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Innate and adaptive immune cells in the tumor microenvironment

Abstract: Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Abstract: The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.