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2. Altered ligands reveal limited plasticity in the T cell response to a pathogenic epitope.

Author

Pingel, S, Launois, P, Fowell, DJ, Turck, CW, Southwood, S, Sette, A, Glaichenhaus, N, Louis, JA, and Locksley, RM

Subjects
Th2 Cells, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mice, Leishmania major, Leishmaniasis, Cutaneous, Disease Susceptibility, Peptide Fragments, Receptors, Antigen, T-Cell, alpha-beta, Protozoan Proteins, Recombinant Fusion Proteins, Interleukin-4, Antigens, Protozoan, Histocompatibility Antigens Class II, Epitopes, Superantigens, Ligands, Amino Acid Substitution, Lymphocyte Activation, Immune Tolerance, Immunity, Cellular, Amino Acid Sequence, Molecular Sequence Data, Female, Interferon-gamma, CD4(+) T cell subsets, altered peptide ligands, LACK antigen, Inbred BALB C, Inbred C57BL, Transgenic, Leishmaniasis, Cutaneous, Receptors, Antigen, T-Cell, alpha-beta, Antigens, Protozoan, Immunity, Cellular, Medical and Health Sciences, Immunology
Abstract

Experimental leishmaniasis offers a well characterized model of T helper type 1 cell (Th1)-mediated control of infection by an intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells in response to infection and are unable to control parasite dissemination. The early CD4(+) T cell response in these mice is oligoclonal and reflects the expansion of Vbeta4/ Valpha8-bearing T cells in response to a single epitope from the parasite Leishmania homologue of mammalian RACK1 (LACK) antigen. Interleukin 4 (IL-4) generated by these cells is believed to direct the subsequent Th2 response. We used T cells from T cell receptor-transgenic mice expressing such a Vbeta4/Valpha8 receptor to characterize altered peptide ligands with similar affinity for I-Ad. Such altered ligands failed to activate IL-4 production from transgenic LACK-specific T cells or following injection into BALB/c mice. Pretreatment of susceptible mice with altered peptide ligands substantially altered the course of subsequent infection. The ability to confer a healer phenotype on otherwise susceptible mice using altered peptides that differed by a single amino acid suggests limited diversity in the endogenous T cell repertoire recognizing this antigen.

Published
1999

5. Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Author

Martinuzzi, E, Barbosa, S, Daoudlarian, D, Bel Haj Ali, W, Gilet, C, Fillatre, L, Khalfallah, O, Troudet, R, Jamain, S, Fond, G, Sommer, I, Leucht, S, Dazzan, P, McGuire, P, Arango, C, Diaz-Caneja, CM, Fleischhacker, W, Rujescu, D, Glenthøj, B, Winter, I, Kahn, RS, Yolken, R, Lewis, S, Drake, R, Davidovic, L, Leboyer, M, Glaichenhaus, N, OPTiMiSE Study Group, De Hert, Marc, Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Equipe IMAGES-CREATIVE, Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Projet MEDIACODING, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), INSERM U955, équipe 15, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Réseau de coopération scientifique en santé mentale, Fondation FondaMental [Créteil]-Fondation FondaMental [Créteil]-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Psychological Medicine, Psychiatry Department, Adolescent Unit, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University Medical Center, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Immunologie des muqueuses et inflammation, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Réseau de coopération scientifique en santé mentale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
0301 basic medicine, Male, Pediatrics, SYMPTOMS, Internationality, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Physiology, [SDV]Life Sciences [q-bio], law.invention, Cohort Studies, 0302 clinical medicine, Randomized controlled trial, law, 1234567890(), ComputingMilieux_MISCELLANEOUS, Inflammation/metabolism, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, ASSOCIATION, ddc, 3. Good health, Psychiatry and Mental health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cytokines, Female, Biological psychiatry, Antipsychotic Agents, Cohort study, Adult, medicine.medical_specialty, Treatment response, TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES, Adolescent, MEDLINE, 1ST EPISODE, SCHIZOPHRENIA-PATIENTS, Cytokines/blood, Article, lcsh:RC321-571, CYTOKINE ALTERATIONS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, First episode psychosis, MENTAL-DISORDERS, medicine, Humans, AGENTS, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Nicolas Glaichenhaus 1234567890(), Biological Psychiatry, TREATMENT RESPONSE, Inflammation, Psychiatric Status Rating Scales, INTERLEUKIN-15, business.industry, Correction, Psychotic Disorders/blood, 030104 developmental biology, Logistic Models, Psychotic Disorders, Multicenter study, Marion Leboyer, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Psychiatric status rating scales, business, Biomarkers, 030217 neurology & neurosurgery, Antipsychotic Agents/therapeutic use, Biomarkers/blood
Abstract

Early response to first-line antipsychotic treatments is strongly associated with positive long-term symptomatic and functional outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are highly heterogeneous in terms of symptom expression and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. We have used a clustering approach to stratify 325 FEP patients into four clinical subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) scale. Compared to C1B, C2A and C2B patients, those from the C1A subtype exhibited the most severe symptoms and were the most at risk of being non-remitters when treated with the second-generation antipsychotic drug amisulpride. Before treatment, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and inflammation-associated biomarkers therefore validating our stratification approach on external biological measures. Most importantly, in the C1A subtype, but not others, lower serum levels of interleukin (IL)-15, higher serum levels of C-X-C motif chemokine 12 (CXCL12), previous exposure to cytomegalovirus (CMV), use of recreational drugs and being younger were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was good (mean area under the curve (AUC) = 0.73 ± 0.10), and its specificity and sensitivity were 45 ± 0.09% and 83 ± 0.03%, respectively. Further validation and replication of these results in clinical trials would pave the way for the development of a blood-based assisted clinical decision support system in psychosis. ispartof: Translational Psychiatry vol:9 issue:1 pages:1-20 ispartof: location:United States status: published

Published
2019

8. The microbial metabolitep-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Author

Bermudez-Martin, P., primary, Becker, J. A. J., additional, Caramello, N., additional, Fernandez, S. P., additional, Costa-Campos, R., additional, Canaguier, J., additional, Barbosa, S., additional, Martinez-Gili, L., additional, Myridakis, A., additional, Dumas, M.-E., additional, Bruneau, A., additional, Cherbuy, C., additional, Langella, P., additional, Callebert, J., additional, Launay, J.-M., additional, Chabry, J., additional, Barik, J., additional, Le Merrer, J., additional, Glaichenhaus, N., additional, and Davidovic, L., additional

Published
2020
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9. Correction: Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study (Translational Psychiatry, (2019), 9, 1, (20), 10.1038/s41398-018-0366-5)

Author

Martinuzzi, E., Barbosa, S., Daoudlarian, D., Ali, W.B.H., Gilet, C., Fillatre, L., Khalfallah, O., Troudet, R., Jamain, S., Fond, G., Sommer, I., Leucht, S., Dazzan, P., McGuire, P., Arango, C., Diaz-Caneja, C.M., Fleischhacker, W., Rujescu, D., Glenthøj, B., Winter, I., Kahn, R.S., Yolken, R., Lewis, S., Drake, R., Davidovic, L., Leboyer, M., and Glaichenhaus, N.

Published
2019

10. Comparative analysis of the perception of nuclear risk among two populations (expert/non-expert) in France

Author

Perez, Sandra, den Auwer, Christophe, Pourcher, Thierry, Russo, Sandra, Drouot, Cyril, Beccia, Maria Rosa, Greff, Gaëlle, Fiorelli, Franck, Leriche, Audrey, Castagnola, Fréderic, Steichen, Pascale, Carle, Georges, Glaichenhaus, N., Michel, Hervé, Josse, Denis, Pottier, Nicolas, Provitolo, Damienne, Études des Structures, des Processus d’Adaptation et des Changements de l’Espace (ESPACE), Université Côte d'Azur (UCA)-Avignon Université (AU)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Bioénergétique et Ingénierie des Protéines (BIP ), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service Départemental d’Incendie et de Secours des Alpes-Maritimes, Service de Santé et de Secours Médical, Nice, Groupe de Recherche en Droit, Economie et Gestion (GREDEG), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Génétique, physiopathologie et ingénierie du tissu osseux (GéPITOS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Géoazur (GEOAZUR 7329), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), CODIREM, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Avignon Université (AU)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), and Perez, Sandra

Subjects
[SHS.GEO] Humanities and Social Sciences/Geography, [SDE.ES] Environmental Sciences/Environmental and Society, [SHS.GEO]Humanities and Social Sciences/Geography, [SDE.ES]Environmental Sciences/Environmental and Society
Abstract

As part of the UCA JEDI IDEX program, the NR2P2* project brought together a multidisciplinary team to interview 2315 people via an online survey to assess their perception of nuclear risk via 33 questions; International audience; In the context of ecological change and the fight to reduce CO2 emissions, nuclear energy can appear to be an efficient energy source, or at least essential from the perspective of energy diversification. However, it suffers from a poor image and a lack of knowledge among the population, and among young people in particular, who favor the development of renewable energy. We wanted to know exactly what was happening in one of the most nuclearized countries in the world, France. To do this, we interviewed a young, student, "non-expert" population about their knowledge and perceptions of nuclear risk and compared the results with a so-called "expert" population: firefighters, most of whom had received training in radiation protection. Thus, in response to the question "Are you afraid of the nuclear sector?" 68% of students answered yes compared to 49% of firefighters. The reasons for fear are sometimes similar (radioactive waste, contamination over long periods, ageing of power plants), and sometimes divergent due to the better knowledge of the firefighters who had undergone radiological training (out of control, fear of the effects of radioactivity). Science students differed from other students by being more in favor of a partial exit from nuclear power (50%, compared to 12% for students from other disciplines), and by indicating that they were more open than others to the possibility of changing their minds if they had more knowledge on the subject (43%). In terms of behavior, the gaps are, as expected, wide between the 2 populations (students/firefighters): less than half (44%) of students adopt the right reflexes (seeking a confined space, sealing ventilation), 55% would prepare for an evacuation and 84% would keep themselves informed, not through social networks as we might think, but through a state organization in charge of managing the nuclear sector. If an alert were to occur, students report that they would be anxious (42%), frightened (12%) or even panicked (25%), unlike firefighters who would of course behave as expected, be more reasoned, and much less panicked (difference of 21%), although half of them admit that they would still be anxious. The results reveal differentiated profiles between the 2 populations (expert/non-expert) in terms of the association between exposure to radioactivity and the occurrence of cancers, and in the level of confidence in nuclear energy in France.

Published
2019

12. Energie nucléaire, de la radiochimie à la perception publique

Author

M-R, Beccia, Carle, G., Fréderic Castagnola, Gaelle Creff, Christophe den Auwer, Drouot, C., Glaichenhaus, N., Denis Josse, Hervé Michel, Sandra PEREZ, Pourcher, T., Damienne Provitolo, Sandra Russo, Pascale Steichen, Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), UMR E4320 (TIRO-MATOs), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service Départemental d’Incendie et de Secours des Alpes-Maritimes, Service de Santé et de Secours Médical, Nice, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Études des Structures, des Processus d’Adaptation et des Changements de l’Espace (ESPACE), Université Côte d'Azur (UCA)-Avignon Université (AU)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Géoazur (GEOAZUR 6526), Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche en Droit, Economie et Gestion (GREDEG), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CODIREM, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Avignon Université (AU)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
[CHIM]Chemical Sciences, [SHS.GEO]Humanities and Social Sciences/Geography, [SDE.ES]Environmental Sciences/Environmental and Society, [CHIM.RADIO]Chemical Sciences/Radiochemistry
Abstract

International audience; Ce travail a bénéficié d'une aide du gouvernement français, gérée par l'Agence Nationale de la Recherche au titre du projet Investissements d'Avenir UCAJEDI portant la référence n° ANR-15-IDEX-01 JIREC 2018

Published
2018

14. Does the Large T Protein of Polyoma Virus Regulate the Expression of the Cellular myc Gene?

Author

Glaichenhaus, N., Galup, C., Mougneau, E., Cuzin, F., Cooper, M., editor, Goebel, W., editor, Hofschneider, P. H., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Rott, R., editor, Schweiger, H. G., editor, Vogt, P. K., editor, Zinkernagel, R., editor, Potter, Michael, editor, Melchers, Fritz, editor, and Weigert, Martin, editor

Published
1984
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15. Presentation of the protective parasite antigen LACK by Leishmania-infected macrophages

Author

Prina, E., Thierry Lang, Glaichenhaus, N., and Antoine, J. -C

Subjects
Immunology, Immunology and Allergy
Abstract

Macrophages are apparently the only cells that in vivo allow the growth of the intracellular pathogen Leishmania. They are thus generally considered as likely candidates for the presentation of parasite Ag to CD4+ T lymphocytes known to be involved in protective and counterprotective immune responses. In the present study, we examined whether mouse macrophages infected with Leishmania were capable of stimulating T cell hybrids and a T cell clone reacting with the previously identified protective Ag LACK (Leishmania homologue of receptors for Activated C Kinase). This parasite protein is expressed in both promastigote and amastigote stages of Leishmania. We found that IFN-gamma-treated macrophages recently infected with live Leishmania promastigotes were fully competent to activate LACK-reactive T cells. However, at later times of infection, permissive macrophages infected with promastigotes were no longer able to present LACK, in spite of the presence of numerous intracellular parasites. This punctual presentation of LACK was apparently linked with the destruction, at least partial, of the intracellular parasites. In contrast, macrophages infected with live Leishmania amastigotes were always unable to stimulate the LACK-specific T cells. Amastigote-infected macrophages could, however, reactivate the T cells if LACK-delta(1), a recombinant form of LACK, was added as an exogenous protein in the culture medium. Similar results were obtained with all combinations tested involving macrophages from various origins, different activating cytokines (IFN-gamma, granulocyte-macrophage CSF, IL-4), several Leishmania species (L. amazonensis, L. major, L. donovani), and 15 different LACK-reactive T cell hybrids and clones. From these data, it is tempting to propose that the differentiation of promastigotes into amastigotes, which leads to a better survival of the parasites within macrophages, also allows them to go unnoticed by the immune system.

Published
1996

23. Immunotherapy in Non-Small Cell Lung Cancer: Biological Principles and Future Opportunities

Author

Ilie, M., Benzaquen, J., Hofman, V., Lassalle, S., Yazbeck, N., Leroy, S., Heeke, S., Bence, C., Mograbi, B., Glaichenhaus, N., Marquette, C.-H., and Hofman, P.

Abstract

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30–40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

Published
2017
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32. Listeria monocytogenes as a short-lived delivery system for the induction of type 1 cell-mediated immunity against the p36/LACK antigen of Leishmania major.

Author

Soussi, N, Milon, G, Colle, J H, Mougneau, E, Glaichenhaus, N, and Goossens, P L

Abstract

Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands for Leishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4(+) T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible to L. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-gamma)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-gamma-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection with L. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-gamma-secreting Th1 CD4 T lymphocytes.

Published
2000

33. The histological spectrum of visceral leishmaniasis caused by Leishmania infantum MON-1 in acquired immune deficiency syndrome

Author

Hofman, V., Marty, P., Perrin, C., Saint-Paul, M.C., Fichoux, Y.L., Michiels, J.F., Glaichenhaus, N., Pratlong, F., and Hofman, P.

Abstract

Visceral leishmaniasis (VL) due to Leishmania infantum is endemic in Southern France and can be considered as an opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). Co-infection with Leishmania sp. and human immunodeficiency virus (HIV) is emerging, but pathological findings of leishmaniasis in AIDS have been poorly documented, and scattered case reports have include morphological descriptions. The clinicopathologic analysis of 16 patients with HIV and VL were evaluated. The clinical presentation was characteristic of VL, with fever, hepatosplenomegaly, and pancytopenia in 6 patients, and the diagnosis was confirmed by finding amastigotes of Leishmania sp. in bone marrow smears and biopsy specimens. In 4 patients, the initial diagnosis of VL was made fortuitously in gastrointestinal biopsies performed systematically (3 patients) or in case of diarrhea (1 patient). In one duodenal biopsy, Leishmania sp. and Mycobacteria sp. were associated. Liver biopsy allowed the diagnosis of VL in 3 cases. Autopsy was performed in 9 patients, showing a disseminated leishmaniasis with very unusual localizations (adrenal and heart) in 2 cases. Cutaneous leishmaniasis involvement was noted before (4 patients), at the same time (2 patient), or after (1 patient) the diagnosis of VL. Inflammatory infiltrates noted with Leishmania sp. infection were made by CD68 macrophages with (8 patients) or without (8 patients) associated CD8 positive lymphocytes. Immunoperoxidase study using polyclonal anti-Leishmania sp. antibodies contributed to the diagnosis in all cases. Electron microscopy of 2 digestive biopsy specimens showed the ultrastructural characteristics of Leishmania sp. amastigotes. The zymodeme MON-1 of L infantum was identified by isoenzyme electrophoresis in all patients. The mean of CD4 counts was 37/mm^3 at the time of diagnosis, and the mean duration before the death was 8 months. As shown in this study, VL in AIDS can be diagnosed in gastrointestinal or liver biopsies. Diagnosis of VL was made when the CD4 count was very low and was correlated with a poor prognosis.

Published
2000
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34. CD4(+) T cells which react to the Leishmania major LACK antigen rapidly secrete interleukin-4 and are detrimental to the host in resistant B10.D2 mice.

Author

Julia, V and Glaichenhaus, N

Abstract

Leishmania major induces the rapid production of interleukin-4 (IL-4) in both susceptible BALB/c and resistant B10.D2 mice. In both strains, IL-4 is produced by T cells which react to the parasite LACK (for Leishmania homolog of the receptor for activated C kinase) antigen. The rapid production of IL-4 in B10.D2 mice does not confer susceptibility but results in increased parasite burdens.

Published
1999

35. Increased levels of mitochondrial gene expression in rat fibroblast cells immortalized or transformed by viral and cellular oncogenes.

Author

Glaichenhaus, N., Léopold, P., and Cuzin, F.

Abstract

Steady‐state levels of the mitochondrial (mt) mRNA encoding subunit II of cytochrome oxidase (COII) were increased 5‐10 fold in fully transformed cell lines derived from rodent embryonic fibroblasts after transfer of polyoma virus DNA, and in immortalized cell lines established by transfer of plt (polyoma large T protein), E1A (adenovirus) and myc oncogenes. Increased mitochondrial gene expression was not related with active growth per se: it was low in fast‐growing rat embryo cells, and it did not change upon serum starvation and subsequent stimulation of FR3T3 cells. The number of copies of mtDNA did not vary, and different mitochondrial mRNAs and rRNAs were increased in the same proportions, suggesting a change in the rate of accumulation of their common precursor.

Published
1986
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36. Study of a growth hormone‐regulated protein secreted by rat hepatocytes: cDNA cloning, anti‐protease activity and regulation of its synthesis by various hormones.

Author

Le Cam, A., Pages, G., Auberger, P., Le Cam, G., Leopold, P., Benarous, R., and Glaichenhaus, N.

Abstract

GHR‐P63 (‘growth hormone‐regulated protein of 63,000 daltons’) is an acidic glycoprotein secreted by rat hepatocytes whose synthesis is abolished upon hypophysectomy. The sequence of its mRNA including the entire coding and 3′ untranslated regions was determined from a nearly full‐length lambda gt11‐cDNA clone. The sequence contained two ATGs in frame giving rise to two overlapping coding regions which could encode precursor polypeptides of 416 and 406 amino acid residues (MrS = 46549 and 45371). These potential translation initiation codons appeared to be functional both in vitro and in intact cells since two precursors of the correct size were immunoprecipitated as products of mRNA translation. The unglycosylated precursors were converted into intermediate intracellular forms of about 56,000 daltons containing N‐linked oligosaccharide side chains and thereafter into the secretory form of approximately equal to 63,000 daltons. Strong sequence homologies, both at the nucleotide and the amino acid levels were found between GHR‐P63 and several serum protease inhibitors, more particularly mouse contrapsin and human alpha 1‐antichymotrypsin. In agreement with sequence data, GHR‐P63 purified from rat blood by affinity chromatography was found to carry an anti‐trypsin activity. GHR‐P63 mRNA, virtually undetectable in hepatocytes from hypophysectomized rats, could be hormonally re‐induced to subnormal levels both in vivo by treating animals with hormones and in vitro by incubating the defective cells with hormones. Growth hormone was absolutely required but had a weak effect when used alone. Glucocorticoids which had no effect per se, strongly potentiated the action of growth hormone. Nuclear run‐off experiments suggest that hormones regulated GHR‐P63 mRNA levels by acting mostly, if not exclusively, on gene transcription.

Published
1987
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37. Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts.

Author

Matrisian, L.M., Glaichenhaus, N., Gesnel, M.C., and Breathnach, R.

Abstract

We have isolated and sequenced a cloned cDNA corresponding to an mRNA present in significantly higher levels in rat cells transformed by polyoma virus, Rous sarcoma virus, and the cellular oncogene H‐ras than in the normal parental cell lines. The mRNA transcript is also rapidly induced by the polypeptide growth factor epidermal growth factor, providing a new link between oncogenes and growth factors. Both the growth factor and the oncogenes control expression of the corresponding gene at the transcriptional level. Our results point to the existence of intracellular mechanisms that are common to the action of both growth factors and oncogenes.

Published
1985
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39. Paper alert. Immunology

Author

Elliott, T., Bonneville, M., Kruisbeek, A., Walker, P. R., Glaichenhaus, N., Rowland-Jones, S., Jean-Laurent Casanova, Liu, Y., Wood, K., Bushell, A., and Green, A.

Abstract

A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in immunology.

43. Generation of functional HLA-DR*1101 tetramers receptive for loading with pathogen or tumour derived synthetic peptides

Author

Protti Maria, Glaichenhaus Nicholas, Giabbai Barbara, Degano Massimo, Dallegno Eliana, Martinoli Chiara, Cecconi Virginia, Moro Monica, Dellabona Paolo, and Casorati Giulia

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background MHC class I-peptide tetramers are currently utilised to characterize CD8+ T cell responses at single cell level. The generation and use of MHC class II tetramers to study antigen-specific CD4+ T cells appears less straightforward. Most MHC class II tetramers are produced with a homogeneously built-in peptide, reducing greatly their flexibility of use. We attempted the generation of "empty" functional HLA-DR*1101 tetramers, receptive for loading with synthetic peptides by incubation. No such reagent is in fact available for this HLA-DR allele, one of the most frequent in the Caucasian population. Results We compared soluble MHC class II-immunoglobulin fusion proteins (HLA-DR*1101-Ig) with soluble MHC class II protein fused with an optimised Bir site for enzymatic biotynilation (HLA-DR*1101-Bir), both produced in insect cells. The molecules were multimerised by binding fluorochrome-protein A or fluorochrome-streptavidin, respectively. We find that HLA-DR*1101-Bir molecules are superior to the HLA-DR*1101-Ig ones both in biochemical and functional terms. HLA-DR*1101-Bir molecules can be pulsed with at least three different promiscuous peptide epitopes, derived from Tetanus Toxoid, influenza HA and the tumour associated antigen MAGE-3 respectively, to stain specific CD4+ T cells. Both staining temperature and activation state of CD4+ T cells are critical for the binding of peptide-pulsed HLA-DR*1101-Bir to the cognate TCR. Conclusion It is therefore possible to generate a soluble recombinant HLA-DR*1101 backbone that is receptive for loading with different peptides to stain specific CD4+ T cells. As shown for other HLA-DR alleles, we confirm that not all the strategies to produce soluble HLA-DR*1101 multimers are equivalent.

Published
2005
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46. Cord serum cytokines at birth and children's trajectories of mood dysregulation symptoms from 3 to 8 years: The EDEN birth cohort.

Author

Herbein M, Barbosa S, Collet O, Khalfallah O, Navarro M, Bailhache M, Iv N, Aouizerate B, Sutter-Dallay AL, Koehl M, Capuron L, Ellul P, Peyre H, Van der Waerden J, Melchior M, Côté S, Heude B, Glaichenhaus N, Davidovic L, and Galera C

Abstract

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed mother-child dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother-child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF-α cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18-0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies., Competing Interests: We declare none of the authors has any conflict of interest regarding the manuscript “Cord serum cytokines at birth and children's trajectories of mood dysregulation symptoms from 3 to 8 years: the EDEN birth cohort”, (© 2024 The Authors. Published by Elsevier Inc.)

Published
2024
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47. Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial.

Author

Strube W, Aksar A, Bauer I, Barbosa S, Benros M, Blankenstein C, Campana M, Davidovic L, Glaichenhaus N, Falkai P, Görlitz T, Hansbauer M, Heilig D, Khalfallah O, Leboyer M, Martinuzzi E, Mayer S, Moussiopoulou J, Papazova I, Perić N, Wagner E, Schneider-Axmann T, Simon J, and Hasan A

Subjects
Humans, Celecoxib therapeutic use, Double-Blind Method, Treatment Outcome, Cytokines, Antipsychotic Agents adverse effects, Schizophrenia drug therapy
Abstract

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The "Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)" is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044., (© 2022. The Author(s).)

Published
2023
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48. Cytokines as mediators of the associations of prenatal exposure to phenols, parabens, and phthalates with internalizing behaviours at age 3 in boys: A mixture exposure and mediation approach.

Author

Khalfallah O, Barbosa S, Phillippat C, Slama R, Galera C, Heude B, Glaichenhaus N, and Davidovic L

Subjects
Male, Infant, Infant, Newborn, Pregnancy, Female, Humans, Child, Child, Preschool, Parabens, Phenols toxicity, Cytokines, Tumor Necrosis Factor-alpha, Bayes Theorem, Interleukin-6, Prenatal Exposure Delayed Effects chemically induced, Prenatal Exposure Delayed Effects epidemiology, Endocrine Disruptors toxicity, Environmental Pollutants toxicity
Abstract

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Glaichenhaus reports financial support was provided by Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail and Université Côte d'Azur. Davidovic reports financial support was provided by Fondation de France., (Copyright © 2023. Published by Elsevier Inc.)

Published
2023
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49. The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay.

Author

Simon T, Kirk J, Dolezalova N, Guyot M, Panzolini C, Bondue A, Lavergne J, Hugues S, Hypolite N, Saeb-Parsy K, Perkins J, Macia E, Sridhar A, Vervoordeldonk MJ, Glaichenhaus N, Donegá M, and Blancou P

Abstract

The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4 + T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4 + T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1 -/- ). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4 + T-cells, NA released by splenic nerve terminals acts directly onto β2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4 + T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to β2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Simon, Kirk, Dolezalova, Guyot, Panzolini, Bondue, Lavergne, Hugues, Hypolite, Saeb-Parsy, Perkins, Macia, Sridhar, Vervoordeldonk, Glaichenhaus, Donegá and Blancou.)

Published
2023
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50. Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling.

Author

Canali MM, Guyot M, Simon T, Daoudlarian D, Chabry J, Panzolini C, Petit-Paitel A, Hypolite N, Nicolas S, Bourdely P, Schmid-Antomarchi H, Schmid-Alliana A, Soria J, Karimdjee Soilihi B, Hofman P, Prevost-Blondel A, Kato M, Mougneau E, Glaichenhaus N, and Blancou P

Abstract

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought., (© 2023. The Author(s).)

Published
2023
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