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2. Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Author

Hadjadj, Jérôme, Castro, Carla Noemi, Tusseau, Maud, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Aladjidi, Nathalie, Armstrong, Martin, Ashrafian, Houman, Cutcutache, Ioana, Ebetsberger-Dachs, Georg, Elliott, Katherine S, Durieu, Isabelle, Fabien, Nicole, Fusaro, Mathieu, Heeg, Maximilian, Schmitt, Yohan, Bras, Marc, Knight, Julian C, Lega, Jean-Christophe, Lesca, Gaetan, Mathieu, Anne-Laure, Moreews, Marion, Moreira, Baptiste, Nosbaum, Audrey, Page, Matthew, Picard, Cécile, Ronan Leahy, T, Rouvet, Isabelle, Ryan, Ethel, Sanlaville, Damien, Schwarz, Klaus, Skelton, Andrew, Viallard, Jean-Francois, Viel, Sebastien, Villard, Marine, Callebaut, Isabelle, Picard, Capucine, Walzer, Thierry, Ehl, Stephan, Fischer, Alain, Neven, Bénédicte, Belot, Alexandre, and Rieux-Laucat, Frédéric

Subjects
T-Lymphocytes, Humans, Autoimmune Diseases, Cytokines, Pedigree, Age of Onset, Signal Transduction, Autoimmunity, Mutation, Models, Molecular, Adolescent, Adult, Child, Child, Preschool, Female, Male, STAT Transcription Factors, Haploinsufficiency, Suppressor of Cytokine Signaling 1 Protein, Human Genome, Rare Diseases, Clinical Research, Genetics, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system
Abstract

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

Published
2020

3. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Author

Hadjadj, Jérôme, Aladjidi, Nathalie, Fernandes, Helder, Leverger, Guy, Magérus-Chatinet, Aude, Mazerolles, Fabienne, Stolzenberg, Marie-Claude, Jacques, Sidonie, Picard, Capucine, Rosain, Jérémie, Fourrage, Cécile, Hanein, Sylvain, Zarhrate, Mohammed, Pasquet, Marlène, Abou Chahla, Wadih, Barlogis, Vincent, Bertrand, Yves, Pellier, Isabelle, Colomb Bottollier, Elodie, Fouyssac, Fanny, Blouin, Pascale, Thomas, Caroline, Cheikh, Nathalie, Dore, Eric, Pondarre, Corinne, Plantaz, Dominique, Jeziorski, Eric, Millot, Frédéric, Garcelon, Nicolas, Ducassou, Stéphane, Perel, Yves, Leblanc, Thierry, Neven, Bénédicte, Fischer, Alain, and Rieux-Laucat, Frédéric

Published
2019
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4. Regulation of Antigen-Independent Adhesion of CD4 T Cells

Author

Mazerolles, Fabienne, Amblard, F., Lecomte, O., Meloche, S., Barbat, C., Hauss, P., Hivroz, C., Sekaly, R., Fischer, A., Lipsky, Peter E., editor, Rothlein, Robert, editor, Kishimoto, Takashi Kei, editor, Faanes, Ronald B., editor, and Smith, C. Wayne, editor

Published
1993
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6. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Author

Charbit-Henrion, Fabienne, primary, Parlato, Marianna, additional, Hanein, Sylvain, additional, Duclaux-Loras, Rémi, additional, Nowak, Jan, additional, Begue, Bernadette, additional, Rakotobe, Sabine, additional, Bruneau, Julie, additional, Fourrage, Cécile, additional, Alibeu, Olivier, additional, Rieux-Laucat, Frédéric, additional, Lévy, Eva, additional, Stolzenberg, Marie-Claude, additional, Mazerolles, Fabienne, additional, Latour, Sylvain, additional, Lenoir, Christelle, additional, Fischer, Alain, additional, Picard, Capucine, additional, Aloi, Marina, additional, Dias, Jorge Amil, additional, Hariz, Mongi Ben, additional, Bourrier, Anne, additional, Breuer, Christian, additional, Breton, Anne, additional, Bronsky, Jiri, additional, Buderus, Stephan, additional, Cananzi, Mara, additional, Coopman, Stéphanie, additional, Crémilleux, Clara, additional, Dabadie, Alain, additional, Dumant-Forest, Clémentine, additional, Gurkan, Odul Egritas, additional, Fabre, Alexandre, additional, Fischer, Aude, additional, Diaz, Marta German, additional, Gonzalez-Lama, Yago, additional, Goulet, Olivier, additional, Guariso, Graziella, additional, Gurcan, Neslihan, additional, Homan, Matjaz, additional, Hugot, Jean-Pierre, additional, Jeziorski, Eric, additional, Karanika, Evi, additional, Lachaux, Alain, additional, Lewindon, Peter, additional, Lima, Rosa, additional, Magro, Fernando, additional, Major, Janos, additional, Malamut, Georgia, additional, Mas, Emmanuel, additional, Mattyus, Istvan, additional, Mearin, Luisa M, additional, Melek, Jan, additional, Navas-Lopez, Victor Manuel, additional, Paerregaard, Anders, additional, Pelatan, Cecile, additional, Pigneur, Bénédicte, additional, Pais, Isabel Pinto, additional, Rebeuh, Julie, additional, Romano, Claudio, additional, Siala, Nadia, additional, Strisciuglio, Caterina, additional, Tempia-Caliera, Michela, additional, Tounian, Patrick, additional, Turner, Dan, additional, Urbonas, Vaidotas, additional, Willot, Stéphanie, additional, Ruemmele, Frank M, additional, and Cerf-Bensussan, Nadine, additional

Published
2020
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7. Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: A multicentre study

Author

Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Remi, Nowak, Jan, Bègue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Amil Dias, Jorge, Ben Hariz, Mongi, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronski, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Egritas Gurkan, Odul, Fabre, Alexandre, Fischer, Aude, German Diaz, Marta, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Janos, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Anders, Pelatan, Cecile, Pigneur, Bénédicte, Pinto Pais, Isabel, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidotas, Willot, Stéphanie, Ruemmele, Frank, Cerf-Bensussan, Nadine, Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Dias, Jorge Amil, Hariz, Mongi Ben, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronski, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Gurkan, Odul Egrita, Fabre, Alexandre, Fischer, Aude, Diaz, Marta German, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Jano, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa M, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Ander, Pelatan, Cecile, Pigneur, Bénédicte, Pais, Isabel Pinto, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidota, Willot, Stéphanie, Ruemmele, Frank M., Cerf-Bensussan, Nadine, Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), GENIUS Group, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Gastroentérologie-Hépatologie et Nutrition Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Hospital de São João [Porto], Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), University of Messina, Department of Pediatrics, Centre Hospitalier Universitaire Mongi Slim [La Marsa], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), CHU Le MAns, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, paediatric, VEO-IBD, Adolescent, monogenic disorder, Gastroenterology, High-Throughput Nucleotide Sequencing, Infant, Genetics and molecular epidemiology, Inflammatory Bowel Diseases, monogenic disorders, Corrigenda, Cohort Studies, paediatrics, Predictive Value of Tests, Child, Preschool, TNGS, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Age of Onset, Child, Genetics and molecular epidemiology, monogenic disorders, paediatrics, TNGS, VEO-IBD, Gastroenterology, AcademicSubjects/MED00260
Abstract

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: Predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Published
2018

9. PD-L1 is expressed on human activated naive effector CD4+ T cells. Regulation by dendritic cells and regulatory CD4+ T cells.

Author

Mazerolles, Fabienne and Rieux-Laucat, Frédéric

Subjects
*REGULATORY T cells, *T cells, *CELLULAR control mechanisms, *DENDRITIC cells, *CYTOTOXIC T cells, *PROGRAMMED death-ligand 1, *B cells, *TUMOR necrosis factors
Abstract

The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs. [ABSTRACT FROM AUTHOR]

Published
2021
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11. Generation of Functional Regulatory T Cells By FOXP3 Gene Transfer into CD4 T Cells from Scurfy Mice and IPEX Patients

Author

Delville, Marianne, primary, Six, Emmanuelle, additional, Bellier, Florence, additional, Sigrist, Nelly, additional, Zemmour, David, additional, Bessard, Marie-André, additional, Mazerolles, Fabienne, additional, Gross, David, additional, Schambach, Axel, additional, Rieux-Laucat, Frederic, additional, Benoist, Christoph, additional, Andre-Schmutz, Isabelle, additional, and Cavazzana, Marina, additional

Published
2016
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12. 560. Generation of Functional Regulatory T Cells by FOXP3 Gene Transfer into CD4 T Cell from IPEX Patients

Author

Six, Emmanuelle, primary, Sigrist, Nelly, additional, Zemmour, David, additional, Bessard, Marie-Andrée, additional, Mazerolles, Fabienne, additional, Martin, Samia, additional, Mavilio, Fulvio, additional, Rieux-Laucat, Frederic, additional, Benoist, Christophe, additional, André-Schmutz, Isabelle, additional, and Cavazzana, Marina, additional

Published
2016
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13. Ligands of CD4 inhibit the association of phospholipase Cgamma1 with phosphoinositide 3 kinase in T cells: regulation of this association by the phosphoinositide 3 kinase activity

Author

Jauliac, Sébastien, Mazerolles, Fabienne, Jabado, Nada, Pallier, Annaïck, Bernard, Frédéric, Peake, Jane, Fischer, Alain, Hivroz, Claire, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Jauliac, Sebastien, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
CD4-Positive T-Lymphocytes, Molecular Sequence Data, MESH: Antigens, CD4, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Amino Acid Sequence, HIV Envelope Protein gp120, Ligands, Phosphatidylinositol 3-Kinases, MESH: HIV Envelope Protein gp120, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor Cells, Cultured, MESH: Ligands, Humans, Amino Acid Sequence, MESH: Phospholipase C gamma, MESH: Humans, MESH: Molecular Sequence Data, Phospholipase C gamma, MESH: Peptides, MESH: CD4-Positive T-Lymphocytes, HLA-DR Antigens, MESH: 1-Phosphatidylinositol 3-Kinase, MESH: HLA-DR Antigens, Isoenzymes, MESH: Research, Type C Phospholipases, CD4 Antigens, MESH: Phospholipase C, MESH: Isoenzymes, Peptides
Abstract

We have previously shown that CD4 ligands inhibit interleukin-2 (IL-2) production and T cell proliferation in human peripheral CD4+ T lymphocytes, in an MHC-independent way. Two major pathways implicated in T cell activation are inhibited by binding of CD4 ligands to the CD4 molecule, i.e. Ca2+ signaling by phospholipase Cgamma1 (PLCgamma1), and ERK-2 activation, suggesting a p21ras inhibition. We have correlated these inhibitions with the disruption of multifunctional complexes containing PLCgamma1, p120GAP and Sam68, induced by T cell activation. We report here that T cell activation through the TCR/CD3 induces an association of the phosphoinositide 3 kinase (PI3 kinase) with PLCgamma1, both in peripheral CD4+ T lymphocytes and the HUT-78 CD4+ T cell line. PI3 kinase is present in the multifunctional complexes that we have described previously. Preincubation of human peripheral CD4+ T cells and HUT-78 CD4+ T cells with gp160 or a peptide analogue of the HLA class II DR molecule precludes the association of PLCgamma1 with PI3 kinase. We also demonstrate, using two specific inhibitors of PI3 kinase activity (LY294002 and wortmannin), that this activity plays a key role in the association of PLCgamma1 with PI3 kinase. Moreover, we demonstrate the implication of the PI3 kinase activity in the negative signal mediated by HIV gp160 binding to CD4 molecules. We propose that the products of the PI3 kinase are important mediators of the negative signaling induced by the binding of CD4 ligands to the CD4 molecule implicated in the regulation of the formation of multifunctional complexes.

Published
1998

14. Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

Author

Gardès, Pauline, primary, Forveille, Monique, additional, Alyanakian, Marie-Alexandra, additional, Aucouturier, Pierre, additional, Ilencikova, Denisa, additional, Leroux, Dominique, additional, Rahner, Nils, additional, Mazerolles, Fabienne, additional, Fischer, Alain, additional, Kracker, Sven, additional, and Durandy, Anne, additional

Published
2012
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15. Hypomorphic mutation ofZAP70in human results in a late onset immunodeficiency and no autoimmunity

Author

Picard, Capucine, primary, Dogniaux, Stéphanie, additional, Chemin, Karine, additional, Maciorowski, Zofia, additional, Lim, Annick, additional, Mazerolles, Fabienne, additional, Rieux-Laucat, Frédéric, additional, Stolzenberg, Marie-Claude, additional, Debre, Marianne, additional, Magny, Jean-Paul, additional, Le Deist, Françoise, additional, Fischer, Alain, additional, and Hivroz, Claire, additional

Published
2009
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20. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study.

Author

Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, and Dias, Jorge Amil

Published
2021
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28. Primary membrane T cell immunodeficiencies

Author

Deist, Françoise Le, primary, Basile, Geneviève de Saint, additional, Mazerolles, Fabienne, additional, Thoenes, Gabriela, additional, Villartay, Jean-Pierre De, additional, Cerf-Bensussan, Nadine, additional, Lisowska-Grospierre, Barbara, additional, Griscelli, Claude, additional, and Fischer, Alain, additional

Published
1991
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29. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity.

Author

Picard, Capucine, Dogniaux, Stéphanie, Chemin, Karine, Maciorowski, Zofia, Lim, Annick, Mazerolles, Fabienne, Rieux-Laucat, Frédéric, Stolzenberg, Marie-Claude, Debre, Marianne, Magny, Jean-Paul, Le Deist, Françoise, Fischer, Alain, and Hivroz, Claire

Abstract

Complete lack of function of the tyrosine kinase ZAP70 in humans results in a severe immunodeficiency, characterized by a lack of mature CD8 T cells and non-functional CD4 T cells. We report herein an immunodeficiency with an inherited hypomorphic mutation of ZAP70 due to a single G-to-A substitution in a non-coding intron. This mutation introduces a new acceptor splice site and allows low levels of normal alternative splicing and of WT ZAP70 expression. This partial deficiency results in a compromised TCR signaling that was totally restored by increased expression of ZAP70, demonstrating that defective activation of the patient T cells was indeed caused by the low level of ZAP70 expression. This partial ZAP70 deficiency was associated with an attenuated clinical and immunological phenotype as compared with complete ZAP70 deficiency. CD4 helper T-cell populations including, follicular helper T cells, Th1, Th17 and Treg were detected in the blood. Finally, the patient had no manifestation of autoimmunity suggesting that the T-cell tolerogenic functions were not compromised, in contrast to what has been observed in mice carrying hypomorphic mutations of Zap70. This report extends the phenotype spectrum of ZAP70 deficiency with a residual function of ZAP70. [ABSTRACT FROM AUTHOR]

Published
2009
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33. A synthetic peptide mimicking the HLA-DR β2-binding site for CD4 inhibits antigen-independent CD4+ T cell adhesion to B cells and CD4+ T cell activation.

Author

Mazerolles, Fabienne, Barbat, Christiane, and Fischer, Alain

Abstract

We studied the ability of a peptide mimicking the major binding site of HLA-DR β2 for CD4 (i.e. amino acids 134–148) to inhibit the adhesion of CD4+ T cells to B cells and ICAM-1-DR-expressing fibroblasts, as well as the proliferation of TCR-CD3-triggered CD4+ T cells. Peptide DR134–148 blocked CD4+ T cell (but not CD8+ T cell) binding to B cells and to DR+ ICAM-1+ fibroblasts in a concentration-dependent manner. A peptide composed of randomly associated identical amino acid residues had no effect. This inhibitory activity was not additive with the effect of an anti-CD4 antibody, peptide DR35–46 (mimicking another potential binding site of HLA-DR β1 to CD4) or an anti-LFA-1 antibody. Adhesion of a T cell line (HUT78) expressing a mutated form of CD4 unable to bind p56lcktyrosine kinase was not inhibited by peptide DR134–148. In addition, herbimycin A, a tyrosine kinase inhibitor, abrogated the inhibitory activity of DR134–148. Since CD4-MHC class II interactions have been shown to play no detectable role in mediating antigen-independent adhesion in this assay, peptide interactions with CD4 may trigger an off signal down-regulating LFA-1-mediated adhesion. Indeed,adhesion of CD4+ T cells to ICAM-1− fibroblasts was not inhibited by peptide DR134–148, while the same peptide inhibited antigen (protein-pure derivative)-and anti-CD3 antibody-induced CD4 T cell proliferation. These findings suggest that the major sequence involved in the MHC class II interaction with CD4 is sufficient toinduce a downstream negative regulatory signal that is mediated by p56lck, independently of antigen-specificTCR triggering. [ABSTRACT FROM AUTHOR]

Published
1996
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34. GF109203X, a Specific PKC Inhibitor, Abrogates Anti-CD3 Antibody-Induced Upregulation of CD4+T Cell Adhesion to B Cells

Author

Hauss, Pascale, Mazerolles, Fabienne, Hivroz, Claire, Lecomte, Olivia, Barbat, Christlane, and Fischer, Alain

Abstract

Antigen-independent adhesion of CD4+T lymphocytes to Epstein-Barr virus transformed B cells is mainly mediated by LFA-1 (CD11a/CD18) and CD2 molecules. Low-affinity binding of resting T cells can be transiently upregulated by cross-linking of CD3-TCR (T cell receptor) complexes. This inside-out signaling influences integrin (β1 and β2) adhesion capacity. Studies using the nonspecific inhibitor staurosporine have suggested that this phenomenon is dependent on protein kinase C activation. We found that the upregulation of anti-CD3-activated CD4+T cell adhesion was inhibited strongly and in a concentration-dependent manner by GF109203X, a compound described as a potent and selective inhibitor of PKC. Comparative studies showed that GF109203X and staurosporine had similar inhibitory effects on the upregulation of activated CD4+T cell adhesion. However, staurospofine is a nonselective kinase inhibitor. PMA-activated CD4+T cell adhesion was also inhibited by GF109203X. In contrast, passive enhancement of adhesion by treatment with the CD11a-specific antibody NKI-L16 was unaffected by GF109203X. Taken together, these results show that PKC is involved in upregulating the adhesion of CD4+T cells to B cells following activation of the former by CD3 cross-linking. PKC-dependent upregulation of CD4+T cell adhesion to B cells is exclusively LFA-1-dependent, as GF109203X had no additional inhibitory effect on anti-LFA-1 antibody-pretreated T cells activated by the anti-CD3 antibody OKT3 and had no effect on the adhesion of LFA-1(-) CD4+T cells. Finally, PKC inhibition did not alter CD2-mediated adhesion. This points to a limited participation of CD2 in T-B cell interactions after TCR/CD3 cross-linking.

Published
1993
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36. Generation of Functional Regulatory T Cells By FOXP3Gene Transfer into CD4 T Cells from Scurfy Mice and IPEX Patients

Author

Delville, Marianne, Six, Emmanuelle, Bellier, Florence, Sigrist, Nelly, Zemmour, David, Bessard, Marie-André, Mazerolles, Fabienne, Gross, David, Schambach, Axel, Rieux-Laucat, Frederic, Benoist, Christoph, Andre-Schmutz, Isabelle, and Cavazzana, Marina

Abstract

IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked) syndrome is the prototype of primary immunodeficiency with prevailing autoimmunity. The disease is caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. In IPEX patients, the absence of a functional Treg cell compartment leads to the development of multiple autoimmune manifestations (including severe enteropathy, type 1 diabetes and eczema) usually in the first months or years of life.

Published
2016
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37. Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency.

Author

Mazerolles, Fabienne, Picard, Capucine, Kracker, Sven, Fischer, Alain, and Durandy, Anne

Subjects
CD4 antigen, T cells, CELLULAR signal transduction, ANTIBODY formation, LYMPH nodes, GENETIC mutation, CELL populations, CHEMOKINE receptors
Abstract

Background: The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH [TFH] cells) in the lymph node follicles. These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4+CD45RO+CXCR5+ T cells are also found in the blood. Objective: We sought to obtain in vitro a population close to the TFH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation. Methods: CD4+CD45RO+CXCR5+ T cells were isolated from blood and activated by CD3/T-cell receptor. Results: We found that CD4+CD45RO+CXCR5+ activated T cells corresponding to circulating bona fide memory TFH cells and that STAT3-deficient patients have abnormally low numbers of “TFH-like” blood T cells. However, STAT3-deficient TFH cells have much the same phenotypic and functional characteristics as TFH cells from healthy control subjects. The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro. Although the STAT3-deficient TFH cells were also able to help control B cells to produce IgG and IgA, induction of IgG production by naive B cells was impaired. Conclusion: Heterozygous mutations in STAT3 lead to reduced numbers of circulating TFH-like cells, a finding that might account (at least in part) for the observed defect in antibody production. [Copyright &y& Elsevier]

Published
2013
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38. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Author

Olivier Alibeu, P. Tounian, Nadia Siala, Michela Tempia-Caliera, Jean-Pierre Hugot, Sabine Rakotobe, Christelle Lenoir, Anne Breton, Caterina Strisciuglio, Víctor Manuel Navas-López, Jan Melek, Alain Fischer, Frédéric Rieux-Laucat, Marie-Claude Stolzenberg, Eric Jeziorski, Yago González-Lama, Bénédicte Pigneur, Mongi Ben Hariz, Marina Aloi, Sylvain Latour, Fabienne Mazerolles, Christian Breuer, Julie Bruneau, Clara Crémilleux, Cecile Pelatan, Vaidotas Urbonas, Alexandre Fabre, Nadine Cerf-Bensussan, Frank M. Ruemmele, Luisa Mearin, Capucine Picard, Georgia Malamut, Neslihan Gurcan, Anders Paerregaard, Isabel Pinto Pais, Dan Turner, István Máttyus, Julie Rebeuh, Jiri Bronsky, Sylvain Hanein, Peter Lewindon, Rémi Duclaux-Loras, Graziella Guariso, Anne Bourrier, Odul Egritas Gurkan, Janos Major, Stéphanie Willot, Mara Cananzi, Marianna Parlato, Claudio Romano, Alain Lachaux, Matjaz Homan, Jorge Amil Dias, Eva Lévy, A Fischer, Stéphanie Coopman, Jan Krzysztof Nowak, Fernando Magro, Clémentine Dumant-Forest, Stephan Buderus, Bernadette Bègue, Fabienne Charbit-Henrion, Olivier Goulet, Evi Karanika, Alain Dabadie, Emmanuel Mas, Marta German Diaz, Cécile Fourrage, Rosa Lima, Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Dias, Jorge Amil, Hariz, Mongi Ben, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronsky, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Gurkan, Odul Egrita, Fabre, Alexandre, Fischer, Aude, Diaz, Marta German, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Jano, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa M, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Ander, Pelatan, Cecile, Pigneur, Bénédicte, Pais, Isabel Pinto, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidota, Willot, Stéphanie, Ruemmele, Frank M, and Cerf-Bensussan, Nadine

Subjects
VEO-IBD, business.industry, Yield (finance), monogenic IBD, next generation sequencing, very early onset IBD, Gastroenterology, Inflammatory Bowel Diseases, Genetics and molecular epidemiology, Original Articles, General Medicine, monogenic disorders, Bioinformatics, Very early onset, DNA sequencing, paediatrics, Editor's Choice, Multicenter study, TNGS, Medicine, genetics and molecular epidemiology, business
Abstract

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Published
2020

39. Inducing and regulating human naive CD4 + t cell proliferation by different antigen presenting cells.

Author

Mazerolles F and Rieux-Laucat F

Abstract

We have shown in previous studies that naive CD4 + T cells isolated from human peripheral blood are induced to proliferate by CD4 neg CD11c + CD14 neg CD16 neg dendritic cells presenting the superantigen SEE. Since this population is very poorly expressed in blood, we tried to find other antigen presenting cells (APCs) to induce this proliferation. The aim of the previous studies was to investigate the regulation of T cell proliferation in pediatric monogenic autoimmune diseases and the regulation of this proliferation by regulatory T cells (TREGs). Since the blood samples from pediatric patients were very small, it was important to study other APCs that are more commonly present in the blood. In this study we tested different APCs isolated from controls, CD19 + B cells, CD11c + CD14 + and CD11c + CD14 neg monocytes, CD11c + CD14 neg CD16 + and CD16 neg dendritic cells. The different T cell populations, naive effector T cells and regulatory T cells were separated simultaneously from the same sample. We show in these studies that CD19 + B cells, CD14 neg and more specifically CD14 neg CD16 + , are also able to induce T cell proliferation as previously described with CD14 neg CD16 neg DCs, but under different conditions. No proliferation was induced with CD14 + monocytes. However, these three APCs are less potent than CD16 neg and inhibition by TREG is more difficult to detect. In addition, when we test the role of CTLA-4 in the regulation of TEFF proliferation, we observe that for some APCs, the inhibition by CTLA-4 was quite different. No inhibition was observed with CD19 + B cells in contrast to CD11c + CD14 neg CD16 + and CD11c + CD14 neg CD16 neg ., Competing Interests: Declaration of competing interest The authors declare no competing financial interests, (Copyright © 2024. Published by Elsevier B.V.)

Published
2024
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40. Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study.

Author

Charbit-Henrion F, Parlato M, Hanein S, Duclaux-Loras R, Nowak J, Begue B, Rakotobe S, Bruneau J, Fourrage C, Alibeu O, Rieux-Laucat F, Lévy E, Stolzenberg MC, Mazerolles F, Latour S, Lenoir C, Fischer A, Picard C, Aloi M, Dias JA, Hariz MB, Bourrier A, Breuer C, Breton A, Bronsky J, Buderus S, Cananzi M, Coopman S, Crémilleux C, Dabadie A, Dumant-Forest C, Gurkan OE, Fabre A, Fischer A, Diaz MG, Gonzalez-Lama Y, Goulet O, Guariso G, Gurcan N, Homan M, Hugot JP, Jeziorski E, Karanika E, Lachaux A, Lewindon P, Lima R, Magro F, Major J, Malamut G, Mas E, Mattyus I, Mearin LM, Melek J, Navas-Lopez VM, Paerregaard A, Pelatan C, Pigneur B, Pais IP, Rebeuh J, Romano C, Siala N, Strisciuglio C, Tempia-Caliera M, Tounian P, Turner D, Urbonas V, Willot S, Ruemmele FM, and Cerf-Bensussan N

Subjects
Adolescent, Age of Onset, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Inflammatory Bowel Diseases therapy, Male, Predictive Value of Tests, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases etiology
Abstract

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment., Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally., Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES., Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD., (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Published
2018
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