Pascal Rihet - Academia.edu (original) (raw)

Papers by Pascal Rihet

Research paper thumbnail of TAGOOS: genome-wide supervised learning of non-coding loci associated to complex phenotypes

Nucleic Acids Research, May 2, 2019

Genome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to comple... more Genome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to complex phenotypes. Most human SNPs fall in non-coding regions and are likely regulatory SNPs, but linkage disequilibrium (LD) blocks make it difficult to distinguish functional SNPs. Therefore, putative functional SNPs are usually annotated with molecular markers of gene regulatory regions and prioritized with dedicated prediction tools. We integrated associated SNPs, LD blocks and regulatory features into a supervised model called TAGOOS (TAG SNP bOOSting) and computed scores genome-wide. The TAGOOS scores enriched and prioritized unseen associated SNPs with an odds ratio of 4.3 and 3.5 and an area under the curve (AUC) of 0.65 and 0.6 for intronic and intergenic regions, respectively. The TAGOOS score was correlated with the maximal significance of associated SNPs and expression quantitative trait loci (eQTLs) and with the number of biological samples annotated for key regulatory features. Analysis of loci and regions associated to cleft lip and human adult height phenotypes recovered known functional loci and predicted new functional loci enriched in transcriptions factors related to the phenotypes. In conclusion, we trained a supervised model based on associated SNPs to prioritize putative functional regions. The TAGOOS scores, annotations and UCSC genome tracks are available here: https: //tagoos.readthedocs.io.

Research paper thumbnail of The contribution of cell hashing for single-cell analysis of acute leukemia

Research Square (Research Square), Sep 8, 2022

After decades during which the treatment of acute myeloblastic leukemia consisted in cytarabine +... more After decades during which the treatment of acute myeloblastic leukemia consisted in cytarabine + anthracycline, targeted therapies have appeared, rst based on monoclonal antibodies (anti-CD52, anti-CD123) and then on speci c inhibitors of molecular mutations (anti-IDH, IDH2 or FLT3). What should be the place of these therapeutic options considering the tumor heterogeneity inherent to leukemia diagnosis and the clonal drift of which this type of tumor is capable? Targeted drugs would require an analysis of the various therapeutic targets not in the total population but at the individual cell level. Indeed, the prognostic value and therapeutic interest of a given molecular target are certainly not the same if it is a cell in terminal differentiation with low proliferative potential or, on the contrary, a stem cell with strong capacities of both proliferation and self-renewal. However, this cell-by-cell analysis is fraught with several pitfalls. The rst one is scienti c because the comparison of two different single cell analysis

Research paper thumbnail of Immunological Mechanisms of Human Resistance to Schistosome Infection - the Protective Effect of Immunoglobulin-E is Balanced by a Blocking Action of IMMUNOGLOBULIN-G4

HAL (Le Centre pour la Communication Scientifique Directe), 1992

Through a long coevolutionary history with humans, Mycobacterium tuberculosis has developed into ... more Through a long coevolutionary history with humans, Mycobacterium tuberculosis has developed into a highly successful pathogen that infects 23-32% of the world population 1,2 and tuberculosis (TB) is the leading infec tious cause of death 3. Following aerosol exposure to M. tuberculosis, three potential clinical outcomes are possi ble, namely, resistance or early clearance of the bacillus, asymptomatic or latent M. tuberculosis infection (LTBI) that can persist for decades, or symptomatic 'active tuberculosis' , which includes pulmonary disease that can result in further transmission. Recent whole blood transcriptomic profiling 4,5 and advanced lung imaging modalities 6 have provided new insight into the transi tion from subclinical to active TB 7,8. However, why some heavily exposed individuals never acquire, or perhaps immediately eliminate, infection is poorly understood. No reliable test exists that directly detects the presence or absence of M. tuberculosis in asymptomatic individu als. The purified protein derivative (PPD) skin reactivity test measures delayed type hypersensitivity to mycobac terial antigens and has been the gold standard for the diagnosis of LTBI for >100 years 9,10. As PPD is enriched for protein antigens 11 that are not necessarily specific to M. tuberculosis, prior immunization with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) or exposure to non tuberculous mycobacteria can yield false positive results. IFNγ release assays (IGRAs) were developed as a whole blood diagnostic test that measures IFNγ release from M. tuberculosis antigenspecific CD4 + T cells after

Research paper thumbnail of Factors Controlling Resistance to Schistosomiasis in Endemic Area

HAL (Le Centre pour la Communication Scientifique Directe), 1992

International audienceno abstrac

Research paper thumbnail of The Contribution of Multiplexing Single Cell RNA Sequencing in Acute Myeloid Leukemia

Diseases, Jul 12, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Peripheral T-cell lymphoma gene expression profiling and potential therapeutic exploitations

HAL (Le Centre pour la Communication Scientifique Directe), 2010

Expression profiling using DNA microarrays has been very helpful to improve our knowledge of the ... more Expression profiling using DNA microarrays has been very helpful to improve our knowledge of the pathobiology of many tumour types, including lymphomas. Peripheral T-cell lymphomas (PTCL) constitute an heterogeneous group of tumours with different morphologic, immunophenotypic, and clinical characteristics. Their complexity and their low frequency in the western countries have made difficult the identification of molecular events responsible of the development of these tumours. The first studies on expression profiling of PTCL have also revealed heterogeneity at this level, mainly regarding the PTCL NOS subgroup. Different molecular subgroups within PTCL unspecified have been identified associated to different expression profiles. However, the clinical significance of this molecular sub-classification remains to be probed in studies involving larger number of samples. In addition, the expression level of NF-kB pathway genes allowed to differentiate two PTCL subgroups, and this difference could have clinical interest. In general, PTCL expression profiles are difficult to interpret due to the significant proportion of other infiltrating cells accompanying the tumour. However, microarrays are being a helpful tool in the initial task of dissecting the PTCL expression profile.

Research paper thumbnail of Strong Serum Inhibition of Specific Ige Correlated to Competing IGG4, Revealed by a New Methodology in Subjects from a Schistosoma-Mansoni Endemic Area

HAL (Le Centre pour la Communication Scientifique Directe), 1992

Strong serum inhibition of specific IgE correlated to competing IgG4, revealed by a new methodolo... more Strong serum inhibition of specific IgE correlated to competing IgG4, revealed by a new methodology in subjects from a S. mansoni endemic area* A method allowing the immunopurification of human IgE from small volumes of sera with a yield close to 100% (mean = 97.8%; SEM = 0.7) has been developed.The immunopurification eluates were cleared of other class antibodies that could compete with IgE in specific assays. Immunopurification of IgE followed by specific IgE enzyme-linked immunosorbent assay (ELISA) (IM-MEL) was then applied to sera of 160 individuals from an area endemic for Schistosoma mansoni. In comparison with radioimmunosorbent test (RAST) and ELISA performed on unfractionated sera, IMMEL provided the highest specific IgE signals. Furthermore, the best correlations between the specific IgE levels and either the specific basophil histamine release levels (r = O.84;p<1Op4) or the a n t i 3 mansoni skin test values (r = 0.45; p = lop4) were obtained with IMMEL. Measurement of a n t i 3 mansoni IgE levels in immunopurified fractions and in unfractionated sera of these 160 individuals revealed a strong serum inhibition (geometric means of 98.6% and 96.8% for the adult worms and the larvae, respectively) of the specific IgE reactivity in ELISA. This inhibition was correlated with the anti-adult worm and anti-larval IgG4 levels (r = 0.65; p < lop4) and r = 0. 5 8 ;~ < respectively). In contrast, this inhibition did not correlate with the specific IgG1, IgG2, IgG3 and IgM levels. Furthermore, the level of specific IgG4 was clearly lower than that of specific IgGl, suggesting that the major contribution of IgG4 in the competition effect is not due to higher levels but rather to a specificity spectrum close to that of the specific IgE.These results support the idea that a specific function of IgG4 in serum might be to control antigen recognition by IgE and consequently, to regulate anaphylactic reactions and IgE-mediated immunity.

Research paper thumbnail of Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

BMC Genomics, Dec 1, 2007

Background: Microarray analyses allow the identification and assessment of molecular signatures i... more Background: Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results: Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/ 6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion: Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

Research paper thumbnail of Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium falciparum parasitemia

HAL (Le Centre pour la Communication Scientifique Directe), 2008

Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymo... more Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymorphisms have been associated with severe malaria, mild malaria, and parasitemia. Lymphotoxin-alpha gene (LTA) that belongs to the TNF family is one such candidate gene. Here we report the family-based association analysis of a cis-regulatory lymphotoxin-a polymorphism with parasitemia in two independent populations living in Burkina Faso. Analysis of 199 subjects (34 families) living in an urban endemic area revealed the association of the low producing LTA þ 80A allele with reduced parasitemia. Furthermore, there was evidence of significant LTA þ 80-by-age and LTA þ 80-by-gender interactions. In another set of 318 residents (55 families) in a rural endemic area, we found both the association of the low producing LTA þ 80A allele with reduced parasitemia and LTA þ 80-by-age and LTA þ 80-by-gender interactions. This study suggests that LTA þ 80 polymorphism influences parasitemia and acts in an age-and gender-dependent manner.

Research paper thumbnail of Influence of carriage of hemoglobin AS and the Fcg receptor IIa-R131 allele on levels of immunoglobulin G2 antibodies to plasmodium falciparum merozoite antigens in Gabonese children

HAL (Le Centre pour la Communication Scientifique Directe), 2005

Background. To extend our previous findings showing an imbalanced distribution of immunoglobulin ... more Background. To extend our previous findings showing an imbalanced distribution of immunoglobulin G2 (IgG2) antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2) and a higher frequency of infection with multiple P. falciparum strains in Gabonese children with sickle cell trait (hemoglobin AS), human Fcg receptor (FcgR) IIa (CD32) polymorphism and the rate of in vitro invasion of red blood cells (RBCs) from subjects with either hemoglobin AA or AS by multiple P. falciparum strains were investigated. Methods. FcgRIIa mutation at amino acid position 131 (arginine or histidine) was detected by polymerase chain reaction, and in vitro cultures for parasites were used to assess the invasion rate. Results. FcgRIIa polymorphism is normally distributed in this population, with no preferential carriage by children with hemoglobin AS. Lower levels of IgG2 subclass antibodies to MSP2 peptides were independently associated with the FcgRIIa-R 131 allele and with carriage of hemoglobin AS. Our data suggest that IgG3 antibody responses to MSP2 epitopes could be exacerbated by lower IgG2 levels in children with hemoglobin AS. Conclusions. The higher rate of invasion of RBCs in the presence of multiple strains may indicate that several invasion pathways are solicited simultaneously, and the longer persistence of ring forms in RBCs from the subjects with hemoglobin AS might reflect a slower multiplication phase, leading to a longer circulation and enhanced phagocytosis of these nonpathogenic parasite forms. This may contribute to the protection against P. falciparum malaria observed in children with hemoglobin AS. In 1949, Haldane [1] hypothesized that malaria has a strong impact on the human genome. Several decades

Research paper thumbnail of Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack

HAL (Le Centre pour la Communication Scientifique Directe), 2004

Genetic predisposition to malaria has been shown by epidemiological, case-control and linkage stu... more Genetic predisposition to malaria has been shown by epidemiological, case-control and linkage studies. In particular, case-control studies have recently shown association between hemoglobin C and resistance to severe malaria in Mali and to clinical malaria in Burkina Faso. In a longitudinal study of families living in an endemic area, we investigated whether hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. We surveyed 256 individuals (71 parents and 185 sibs) from 53 families during 2 years. Hemoglobin C carriers had less frequent malaria attacks than AA individuals within the same age group (P ¼ 0.01). Since age correlated with malaria attack and parasitemia (P < 0.0001), we took age into account in association analyses. We performed combined linkage and association analyses, which avoid biases due to population structure. Using multi-allelic tests, we evidenced association between hemoglobin genotype and phenotypes related to malarial infection and disease (P < 0.001). We further analyzed individual hemoglobin alleles and detected negative association between hemoglobin C and malaria attack (P ¼ 0.00013). Analyses that took into account confounding factors confirmed the negative association of hemoglobin C with malaria attack (P ¼ 0.0074) and evidenced a negative correlation between hemoglobin C and parasitemia (P ¼ 0.0009). These associations indicate that hemoglobin C reduces parasitemia and confers protection against mild malaria attack.

Research paper thumbnail of Correction: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

PLOS Genetics, Aug 15, 2018

The following information is missing from the Funding section: This study was supported by GRRC (... more The following information is missing from the Funding section: This study was supported by GRRC (https://sfcardio.fr/grrc/sommaire) to CC.

Research paper thumbnail of The contribution of multiplexing single cell RNA sequencing in acute myeloid leukemia

After decades during which the treatment of acute myeloid leukemia consisted in cytarabine + anth... more After decades during which the treatment of acute myeloid leukemia consisted in cytarabine + anthracycline, targeted therapies have appeared, first based on monoclonal antibodies (anti-CD52, anti-CD123) and then on specific inhibitors of molecular mutations (anti-IDH, IDH2 or FLT3). What should be the place of these therapeutic options considering the tumor heterogeneity inherent to leukemia diagnosis and the clonal drift of which this type of tumor is capable? Targeted drugs would require an analysis of the various therapeutic targets not in the total population but at the individual cell level. Indeed, the prognostic value and therapeutic interest of a given molecular target are certainly not the same if it is a cell in terminal differentiation with low proliferative potential or, on the contrary, a stem cell with strong capacities of both proliferation and self-renewal. However, this cell-by-cell analysis is fraught with several pitfalls. The first one is scientific because the c...

Research paper thumbnail of Reviewed by

doi: 10.3389/fmicb.2014.00255 Identification of overexpressed genes in Sodalis glossinidius inhab... more doi: 10.3389/fmicb.2014.00255 Identification of overexpressed genes in Sodalis glossinidius inhabiting trypanosome-infected self-cured tsetse flies

Research paper thumbnail of Schistosoma-Mansoni P-37 Antigen - Identification by Antibodies from Resistant Subjects and Molecular-Cloning

International audienceno abstrac

Research paper thumbnail of A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation

Experimental hematology, Jun 7, 2018

Autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment in multipl... more Autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment in multiple myeloma and relapsed or refractory lymphomas. After auto-HSCT, hematologic reconstitution and infectious complications are the main two critical issues. Though many patients develop infectious complications after therapeutic intensification, it remains impossible to predict infection for each individual. The goal of this work was to determine and identify a predictive transcriptomic signature of systemic inflammatory response syndrome (SIRS) and/or sepsis in patients receiving auto-HSCT. High throughput transcriptomic and bioinformatics analysis were performed to analyze gene expression modulation in peripheral blood mononuclear cells (PBMCs) in 21 patients undergoing auto-HSCT for hematological malignancies (lymphoma or multiple myeloma [MM]). Transcriptomic analysis of PBMCs samples collected just after conditioning regimen identified an eleven genes signature (CHAT, CNN3, ANKRD42, L...

Research paper thumbnail of Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis

Immunologic research, 2016

Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia... more Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCR(bright)) or low levels (NCR(dull)) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a spe...

Research paper thumbnail of Approaches combining mice and Drosophila melanogaster models to decipher human sepsis

Critical Care, 2014

Introduction: During the course of systemic inflammation, most of the immune cell types get activ... more Introduction: During the course of systemic inflammation, most of the immune cell types get activated to a certain degree as part of, or contributing to, the cascade of physiopathological events. Whether for some cells, classically phagocytes of the innate immune system, it is clear that direct sensing of pathogen-associated molecular patterns leads to activation initiating systemic inflammation, the picture is not so clear for natural killer (NK) cells. While NK cells have been shown to express toll-like receptors (TLR), the role of these receptors on NKs during systemic inflammation has not been directly addressed. Methods: To directly assess the role of TLR expression on NK cells we used an adoptive transfer model in which NKs purified from the spleens of WT, TLR4KO and TLR2/4DKO mice were transferred intravenously to RAG2-/γc-/-(devoid of T, B and NK cells). Five days after reconstitution the mice were challenged intraperitoneally with conventional or TLR-grade lipopolysaccharide (LPS). Immune cell activation and production of IFNγ by NK cells was determined after 6 hours by FACS analysis. Results: We observed no differences in reconstitution of the recipient mice with NK cells from different backgrounds suggesting no difference in trafficking and survival of the transferred cells. At 6 hours after LPS challenge, WT, TLR4KO or TLR2/4DKO NK cells recovered from the spleen and lungs of RAG2-/γc-/mice showed comparable levels of CD69 activation marker expression. Intracellular labeling for IFNγ in NK cells also revealed no significant differences. Conclusion: Whether there is a role for direct TLR signaling on NK cells remains the objective of further investigations; however, our data show that in the course of a systemic inflammatory process, like endotoxinemia, the expression of TLR2 and TLR4 by NK cells makes no difference in terms of their activation and secretion of IFNγ P2 Role of 6-hour, 12-hour, and 24-hour lactate clearance in mortality of severe sepsis and septic shock patients.

Research paper thumbnail of Facteurs génétiques et immunologiques déterminant la résistance à la bilharziose en région d'endémie

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

Journal of Infectious Diseases, 1993

The hypothesis of an association between human resistance to reinfection by the parasite Schistos... more 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.

Research paper thumbnail of TAGOOS: genome-wide supervised learning of non-coding loci associated to complex phenotypes

Nucleic Acids Research, May 2, 2019

Genome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to comple... more Genome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to complex phenotypes. Most human SNPs fall in non-coding regions and are likely regulatory SNPs, but linkage disequilibrium (LD) blocks make it difficult to distinguish functional SNPs. Therefore, putative functional SNPs are usually annotated with molecular markers of gene regulatory regions and prioritized with dedicated prediction tools. We integrated associated SNPs, LD blocks and regulatory features into a supervised model called TAGOOS (TAG SNP bOOSting) and computed scores genome-wide. The TAGOOS scores enriched and prioritized unseen associated SNPs with an odds ratio of 4.3 and 3.5 and an area under the curve (AUC) of 0.65 and 0.6 for intronic and intergenic regions, respectively. The TAGOOS score was correlated with the maximal significance of associated SNPs and expression quantitative trait loci (eQTLs) and with the number of biological samples annotated for key regulatory features. Analysis of loci and regions associated to cleft lip and human adult height phenotypes recovered known functional loci and predicted new functional loci enriched in transcriptions factors related to the phenotypes. In conclusion, we trained a supervised model based on associated SNPs to prioritize putative functional regions. The TAGOOS scores, annotations and UCSC genome tracks are available here: https: //tagoos.readthedocs.io.

Research paper thumbnail of The contribution of cell hashing for single-cell analysis of acute leukemia

Research Square (Research Square), Sep 8, 2022

After decades during which the treatment of acute myeloblastic leukemia consisted in cytarabine +... more After decades during which the treatment of acute myeloblastic leukemia consisted in cytarabine + anthracycline, targeted therapies have appeared, rst based on monoclonal antibodies (anti-CD52, anti-CD123) and then on speci c inhibitors of molecular mutations (anti-IDH, IDH2 or FLT3). What should be the place of these therapeutic options considering the tumor heterogeneity inherent to leukemia diagnosis and the clonal drift of which this type of tumor is capable? Targeted drugs would require an analysis of the various therapeutic targets not in the total population but at the individual cell level. Indeed, the prognostic value and therapeutic interest of a given molecular target are certainly not the same if it is a cell in terminal differentiation with low proliferative potential or, on the contrary, a stem cell with strong capacities of both proliferation and self-renewal. However, this cell-by-cell analysis is fraught with several pitfalls. The rst one is scienti c because the comparison of two different single cell analysis

Research paper thumbnail of Immunological Mechanisms of Human Resistance to Schistosome Infection - the Protective Effect of Immunoglobulin-E is Balanced by a Blocking Action of IMMUNOGLOBULIN-G4

HAL (Le Centre pour la Communication Scientifique Directe), 1992

Through a long coevolutionary history with humans, Mycobacterium tuberculosis has developed into ... more Through a long coevolutionary history with humans, Mycobacterium tuberculosis has developed into a highly successful pathogen that infects 23-32% of the world population 1,2 and tuberculosis (TB) is the leading infec tious cause of death 3. Following aerosol exposure to M. tuberculosis, three potential clinical outcomes are possi ble, namely, resistance or early clearance of the bacillus, asymptomatic or latent M. tuberculosis infection (LTBI) that can persist for decades, or symptomatic 'active tuberculosis' , which includes pulmonary disease that can result in further transmission. Recent whole blood transcriptomic profiling 4,5 and advanced lung imaging modalities 6 have provided new insight into the transi tion from subclinical to active TB 7,8. However, why some heavily exposed individuals never acquire, or perhaps immediately eliminate, infection is poorly understood. No reliable test exists that directly detects the presence or absence of M. tuberculosis in asymptomatic individu als. The purified protein derivative (PPD) skin reactivity test measures delayed type hypersensitivity to mycobac terial antigens and has been the gold standard for the diagnosis of LTBI for >100 years 9,10. As PPD is enriched for protein antigens 11 that are not necessarily specific to M. tuberculosis, prior immunization with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) or exposure to non tuberculous mycobacteria can yield false positive results. IFNγ release assays (IGRAs) were developed as a whole blood diagnostic test that measures IFNγ release from M. tuberculosis antigenspecific CD4 + T cells after

Research paper thumbnail of Factors Controlling Resistance to Schistosomiasis in Endemic Area

HAL (Le Centre pour la Communication Scientifique Directe), 1992

International audienceno abstrac

Research paper thumbnail of The Contribution of Multiplexing Single Cell RNA Sequencing in Acute Myeloid Leukemia

Diseases, Jul 12, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Peripheral T-cell lymphoma gene expression profiling and potential therapeutic exploitations

HAL (Le Centre pour la Communication Scientifique Directe), 2010

Expression profiling using DNA microarrays has been very helpful to improve our knowledge of the ... more Expression profiling using DNA microarrays has been very helpful to improve our knowledge of the pathobiology of many tumour types, including lymphomas. Peripheral T-cell lymphomas (PTCL) constitute an heterogeneous group of tumours with different morphologic, immunophenotypic, and clinical characteristics. Their complexity and their low frequency in the western countries have made difficult the identification of molecular events responsible of the development of these tumours. The first studies on expression profiling of PTCL have also revealed heterogeneity at this level, mainly regarding the PTCL NOS subgroup. Different molecular subgroups within PTCL unspecified have been identified associated to different expression profiles. However, the clinical significance of this molecular sub-classification remains to be probed in studies involving larger number of samples. In addition, the expression level of NF-kB pathway genes allowed to differentiate two PTCL subgroups, and this difference could have clinical interest. In general, PTCL expression profiles are difficult to interpret due to the significant proportion of other infiltrating cells accompanying the tumour. However, microarrays are being a helpful tool in the initial task of dissecting the PTCL expression profile.

Research paper thumbnail of Strong Serum Inhibition of Specific Ige Correlated to Competing IGG4, Revealed by a New Methodology in Subjects from a Schistosoma-Mansoni Endemic Area

HAL (Le Centre pour la Communication Scientifique Directe), 1992

Strong serum inhibition of specific IgE correlated to competing IgG4, revealed by a new methodolo... more Strong serum inhibition of specific IgE correlated to competing IgG4, revealed by a new methodology in subjects from a S. mansoni endemic area* A method allowing the immunopurification of human IgE from small volumes of sera with a yield close to 100% (mean = 97.8%; SEM = 0.7) has been developed.The immunopurification eluates were cleared of other class antibodies that could compete with IgE in specific assays. Immunopurification of IgE followed by specific IgE enzyme-linked immunosorbent assay (ELISA) (IM-MEL) was then applied to sera of 160 individuals from an area endemic for Schistosoma mansoni. In comparison with radioimmunosorbent test (RAST) and ELISA performed on unfractionated sera, IMMEL provided the highest specific IgE signals. Furthermore, the best correlations between the specific IgE levels and either the specific basophil histamine release levels (r = O.84;p<1Op4) or the a n t i 3 mansoni skin test values (r = 0.45; p = lop4) were obtained with IMMEL. Measurement of a n t i 3 mansoni IgE levels in immunopurified fractions and in unfractionated sera of these 160 individuals revealed a strong serum inhibition (geometric means of 98.6% and 96.8% for the adult worms and the larvae, respectively) of the specific IgE reactivity in ELISA. This inhibition was correlated with the anti-adult worm and anti-larval IgG4 levels (r = 0.65; p < lop4) and r = 0. 5 8 ;~ < respectively). In contrast, this inhibition did not correlate with the specific IgG1, IgG2, IgG3 and IgM levels. Furthermore, the level of specific IgG4 was clearly lower than that of specific IgGl, suggesting that the major contribution of IgG4 in the competition effect is not due to higher levels but rather to a specificity spectrum close to that of the specific IgE.These results support the idea that a specific function of IgG4 in serum might be to control antigen recognition by IgE and consequently, to regulate anaphylactic reactions and IgE-mediated immunity.

Research paper thumbnail of Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

BMC Genomics, Dec 1, 2007

Background: Microarray analyses allow the identification and assessment of molecular signatures i... more Background: Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results: Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/ 6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion: Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

Research paper thumbnail of Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium falciparum parasitemia

HAL (Le Centre pour la Communication Scientifique Directe), 2008

Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymo... more Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymorphisms have been associated with severe malaria, mild malaria, and parasitemia. Lymphotoxin-alpha gene (LTA) that belongs to the TNF family is one such candidate gene. Here we report the family-based association analysis of a cis-regulatory lymphotoxin-a polymorphism with parasitemia in two independent populations living in Burkina Faso. Analysis of 199 subjects (34 families) living in an urban endemic area revealed the association of the low producing LTA þ 80A allele with reduced parasitemia. Furthermore, there was evidence of significant LTA þ 80-by-age and LTA þ 80-by-gender interactions. In another set of 318 residents (55 families) in a rural endemic area, we found both the association of the low producing LTA þ 80A allele with reduced parasitemia and LTA þ 80-by-age and LTA þ 80-by-gender interactions. This study suggests that LTA þ 80 polymorphism influences parasitemia and acts in an age-and gender-dependent manner.

Research paper thumbnail of Influence of carriage of hemoglobin AS and the Fcg receptor IIa-R131 allele on levels of immunoglobulin G2 antibodies to plasmodium falciparum merozoite antigens in Gabonese children

HAL (Le Centre pour la Communication Scientifique Directe), 2005

Background. To extend our previous findings showing an imbalanced distribution of immunoglobulin ... more Background. To extend our previous findings showing an imbalanced distribution of immunoglobulin G2 (IgG2) antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2) and a higher frequency of infection with multiple P. falciparum strains in Gabonese children with sickle cell trait (hemoglobin AS), human Fcg receptor (FcgR) IIa (CD32) polymorphism and the rate of in vitro invasion of red blood cells (RBCs) from subjects with either hemoglobin AA or AS by multiple P. falciparum strains were investigated. Methods. FcgRIIa mutation at amino acid position 131 (arginine or histidine) was detected by polymerase chain reaction, and in vitro cultures for parasites were used to assess the invasion rate. Results. FcgRIIa polymorphism is normally distributed in this population, with no preferential carriage by children with hemoglobin AS. Lower levels of IgG2 subclass antibodies to MSP2 peptides were independently associated with the FcgRIIa-R 131 allele and with carriage of hemoglobin AS. Our data suggest that IgG3 antibody responses to MSP2 epitopes could be exacerbated by lower IgG2 levels in children with hemoglobin AS. Conclusions. The higher rate of invasion of RBCs in the presence of multiple strains may indicate that several invasion pathways are solicited simultaneously, and the longer persistence of ring forms in RBCs from the subjects with hemoglobin AS might reflect a slower multiplication phase, leading to a longer circulation and enhanced phagocytosis of these nonpathogenic parasite forms. This may contribute to the protection against P. falciparum malaria observed in children with hemoglobin AS. In 1949, Haldane [1] hypothesized that malaria has a strong impact on the human genome. Several decades

Research paper thumbnail of Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack

HAL (Le Centre pour la Communication Scientifique Directe), 2004

Genetic predisposition to malaria has been shown by epidemiological, case-control and linkage stu... more Genetic predisposition to malaria has been shown by epidemiological, case-control and linkage studies. In particular, case-control studies have recently shown association between hemoglobin C and resistance to severe malaria in Mali and to clinical malaria in Burkina Faso. In a longitudinal study of families living in an endemic area, we investigated whether hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. We surveyed 256 individuals (71 parents and 185 sibs) from 53 families during 2 years. Hemoglobin C carriers had less frequent malaria attacks than AA individuals within the same age group (P ¼ 0.01). Since age correlated with malaria attack and parasitemia (P < 0.0001), we took age into account in association analyses. We performed combined linkage and association analyses, which avoid biases due to population structure. Using multi-allelic tests, we evidenced association between hemoglobin genotype and phenotypes related to malarial infection and disease (P < 0.001). We further analyzed individual hemoglobin alleles and detected negative association between hemoglobin C and malaria attack (P ¼ 0.00013). Analyses that took into account confounding factors confirmed the negative association of hemoglobin C with malaria attack (P ¼ 0.0074) and evidenced a negative correlation between hemoglobin C and parasitemia (P ¼ 0.0009). These associations indicate that hemoglobin C reduces parasitemia and confers protection against mild malaria attack.

Research paper thumbnail of Correction: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

PLOS Genetics, Aug 15, 2018

The following information is missing from the Funding section: This study was supported by GRRC (... more The following information is missing from the Funding section: This study was supported by GRRC (https://sfcardio.fr/grrc/sommaire) to CC.

Research paper thumbnail of The contribution of multiplexing single cell RNA sequencing in acute myeloid leukemia

After decades during which the treatment of acute myeloid leukemia consisted in cytarabine + anth... more After decades during which the treatment of acute myeloid leukemia consisted in cytarabine + anthracycline, targeted therapies have appeared, first based on monoclonal antibodies (anti-CD52, anti-CD123) and then on specific inhibitors of molecular mutations (anti-IDH, IDH2 or FLT3). What should be the place of these therapeutic options considering the tumor heterogeneity inherent to leukemia diagnosis and the clonal drift of which this type of tumor is capable? Targeted drugs would require an analysis of the various therapeutic targets not in the total population but at the individual cell level. Indeed, the prognostic value and therapeutic interest of a given molecular target are certainly not the same if it is a cell in terminal differentiation with low proliferative potential or, on the contrary, a stem cell with strong capacities of both proliferation and self-renewal. However, this cell-by-cell analysis is fraught with several pitfalls. The first one is scientific because the c...

Research paper thumbnail of Reviewed by

doi: 10.3389/fmicb.2014.00255 Identification of overexpressed genes in Sodalis glossinidius inhab... more doi: 10.3389/fmicb.2014.00255 Identification of overexpressed genes in Sodalis glossinidius inhabiting trypanosome-infected self-cured tsetse flies

Research paper thumbnail of Schistosoma-Mansoni P-37 Antigen - Identification by Antibodies from Resistant Subjects and Molecular-Cloning

International audienceno abstrac

Research paper thumbnail of A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation

Experimental hematology, Jun 7, 2018

Autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment in multipl... more Autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment in multiple myeloma and relapsed or refractory lymphomas. After auto-HSCT, hematologic reconstitution and infectious complications are the main two critical issues. Though many patients develop infectious complications after therapeutic intensification, it remains impossible to predict infection for each individual. The goal of this work was to determine and identify a predictive transcriptomic signature of systemic inflammatory response syndrome (SIRS) and/or sepsis in patients receiving auto-HSCT. High throughput transcriptomic and bioinformatics analysis were performed to analyze gene expression modulation in peripheral blood mononuclear cells (PBMCs) in 21 patients undergoing auto-HSCT for hematological malignancies (lymphoma or multiple myeloma [MM]). Transcriptomic analysis of PBMCs samples collected just after conditioning regimen identified an eleven genes signature (CHAT, CNN3, ANKRD42, L...

Research paper thumbnail of Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis

Immunologic research, 2016

Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia... more Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCR(bright)) or low levels (NCR(dull)) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a spe...

Research paper thumbnail of Approaches combining mice and Drosophila melanogaster models to decipher human sepsis

Critical Care, 2014

Introduction: During the course of systemic inflammation, most of the immune cell types get activ... more Introduction: During the course of systemic inflammation, most of the immune cell types get activated to a certain degree as part of, or contributing to, the cascade of physiopathological events. Whether for some cells, classically phagocytes of the innate immune system, it is clear that direct sensing of pathogen-associated molecular patterns leads to activation initiating systemic inflammation, the picture is not so clear for natural killer (NK) cells. While NK cells have been shown to express toll-like receptors (TLR), the role of these receptors on NKs during systemic inflammation has not been directly addressed. Methods: To directly assess the role of TLR expression on NK cells we used an adoptive transfer model in which NKs purified from the spleens of WT, TLR4KO and TLR2/4DKO mice were transferred intravenously to RAG2-/γc-/-(devoid of T, B and NK cells). Five days after reconstitution the mice were challenged intraperitoneally with conventional or TLR-grade lipopolysaccharide (LPS). Immune cell activation and production of IFNγ by NK cells was determined after 6 hours by FACS analysis. Results: We observed no differences in reconstitution of the recipient mice with NK cells from different backgrounds suggesting no difference in trafficking and survival of the transferred cells. At 6 hours after LPS challenge, WT, TLR4KO or TLR2/4DKO NK cells recovered from the spleen and lungs of RAG2-/γc-/mice showed comparable levels of CD69 activation marker expression. Intracellular labeling for IFNγ in NK cells also revealed no significant differences. Conclusion: Whether there is a role for direct TLR signaling on NK cells remains the objective of further investigations; however, our data show that in the course of a systemic inflammatory process, like endotoxinemia, the expression of TLR2 and TLR4 by NK cells makes no difference in terms of their activation and secretion of IFNγ P2 Role of 6-hour, 12-hour, and 24-hour lactate clearance in mortality of severe sepsis and septic shock patients.

Research paper thumbnail of Facteurs génétiques et immunologiques déterminant la résistance à la bilharziose en région d'endémie

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

Journal of Infectious Diseases, 1993

The hypothesis of an association between human resistance to reinfection by the parasite Schistos... more 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.