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TNF family ligands BAFF, APRIL and EDA

English title TNF family ligands BAFF, APRIL and EDA
Applicant Schneider Pascal
Number 156961
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.11.2014 - 31.10.2017
Approved amount 499'000.00
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All Disciplines (4)

Discipline
Biochemistry
Immunology, Immunopathology
Molecular Biology
Embryology, Developmental Biology

Keywords (5)

TNF; ectodermal dysplasia; receptor heteromers; B cells; therapy

Lay Summary (French)

Lead
Les ligands BAFF et APRIL sont importants pour la fonction du système immunitaire (biologie des lymphocytes B), alors qu’EDA contrôle le développement des phanères (poils, dents et diverses glandes). Nous étudions les aspects moléculaires de base de ces ligands de la famille du TNF, notamment la manière dont ils activent leurs voies de signalisation respectives in vitro et in vivo. L’accent est également mis sur l’exploitation clinique des résultats.
Lay summary

Les ligands BAFF et APRIL sont importants pour la fonction du système immunitaire (biologie des lymphocytes B), alors qu’EDA contrôle le développement des phanères (poils, dents et diverses glandes). Nous étudions les aspects moléculaires de base de ces ligands de la famille du TNF, notamment la manière dont ils activent leurs voies de signalisation respectives in vitro et in vivo. L’accent est également mis sur l’exploitation clinique des résultats.

Contenu et objectifs du travail de recherche

L’inactivation génétique d’EDA cause la dysplasie ectodermique hypohidrotique liée à l’X (XLHED) pour laquelle notre groupe a développé une thérapie -actuellement en essai clinique de phase II- consistant à administrer EDA recombinant durant le développement. Le projet porte sur la physiologie d’EDA, sur l’amélioration des méthodes d’administration et sur l’implication éventuelle d’EDA dans d’autres pathologies, notamment cutanées. D’autre part, BAFF et d’APRIL sont produits de manière excessive dans des maladies auto-immunes, suggérant un lien avec la production d’auto-anticorps. Dans ce cadre, nos recherches s’intéressent à la biochimie et à la physiopathologie des différentes formes de BAFF et d’APRIL et à leur susceptibilité à différents inhibiteurs. Une attention particulière est apportée à la caractérisation de la dichotomie qui existe d’une part entre la liaison, et d’autre part entre l’activation d’un récepteur par son ligand.

 

Contexte scientifique et social du projet de recherche

Les aspects fondamentaux de cette recherche vont permettre une meilleure compréhension globale du mode d’action des ligands de la famille du TNF, ligands qui représentent des cibles cliniques d’importance. Les aspects plus appliqués sont destinés à favoriser le succès, voire l’extension de thérapies pour des pathologies en manque de traitements.

Direct link to Lay Summary Last update: 24.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero.
Jia Shihai, Zhou Jing, Fanelli Christopher, Wee Yinshen, Bonds John, Schneider Pascal, Mues Gabriele, D'Souza Rena N (2017), Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero., in Development (Cambridge, England), 144(20), 3819-3828.
Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice.
Jia S, Zhou J, Wee Y, Mikkola M L, Schneider P, D'Souza R N (2017), Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice., in Journal of dental research, 96(11), 1282-1289.
αVβ3 Integrin regulates astrocyte reactivity.
Lagos-Cabré Raúl, Alvarez Alvaro, Kong Milene, Burgos-Bravo Francesca, Cárdenas Areli, Rojas-Mancilla Edgardo, Pérez-Nuñez Ramón, Herrera-Molina Rodrigo, Rojas Fabiola, Schneider Pascal, Herrera-Marschitz Mario, Quest Andrew F G, van Zundert Brigitte, Leyton Lisette (2017), αVβ3 Integrin regulates astrocyte reactivity., in Journal of neuroinflammation, 14(1), 194-194.
A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells.
Haselmayer Philipp, Vigolo Michele, Nys Josquin, Schneider Pascal, Hess Henry (2017), A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells., in European journal of immunology, 47(6), 1075-1085.
TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus.
Tran Ngoc Lan, Schneider Pascal, Santiago-Raber Marie-Laure (2017), TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus., in European journal of immunology, 47(4), 713-723.
Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway.
Maldonado H, Calderon C, Burgos-Bravo F, Kobler O, Zuschratter W, Ramirez O, Härtel S, Schneider P, Quest A F G, Herrera-Molina R, Leyton L (2017), Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway., in Biochimica et biophysica acta, 1864(2), 243-254.
N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death.
Dufour Florent, Rattier Thibault, Shirley Sarah, Picarda Gaelle, Constantinescu Andrei Alexandru, Morlé Aymeric, Zakaria Al Batoul, Marcion Guillaume, Causse Sebastien, Szegezdi Eva, Zajonc Dirk Michael, Seigneuric Renaud, Guichard Gilles, Gharbi Tijani, Picaud Fabien, Herlem Guillaume, Garrido Carmen, Schneider Pascal, Benedict Chris Alan, Micheau Olivier (2017), N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death., in Cell death and differentiation, 24(3), 500-510.
Ectodysplasin A in Biological Fluids and Diagnosis of Ectodermal Dysplasia.
Podzus J, Kowalczyk-Quintas C, Schuepbach-Mallepell S, Willen L, Staehlin G, Vigolo M, Tardivel A, Headon D, Kirby N, Mikkola M L, Schneider H, Schneider P (2017), Ectodysplasin A in Biological Fluids and Diagnosis of Ectodermal Dysplasia., in Journal of dental research, 96(2), 217-224.
CXCL-8/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL.
Manfroi Benoit, McKee Thomas, Mayol Jean Francois, Tabruyn Sebastien, Moret Sebastien, Villiers Christian, Righini Christian, Dyer Martin, Callanan Mary, Schneider Pascal, Tzankov Alexandar, Matthes Thomas, Sturm Nathalie, Huard Bertrand (2017), CXCL-8/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL., in Cancer research, 77(5), 1097-1107.
BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells.
Smulski Cristian R, Kury Patrick, Seidel Lea M, Staiger Hannah S, Edinger Anna K, Willen Laure, Seidl Maximilan, Hess Henry, Salzer Ulrich, Rolink Antonius G, Rizzi Marta, Schneider Pascal, Eibel Hermann (2017), BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells., in Cell reports, 18(9), 2189-2202.
Hetero-oligomerization between the TNF receptor superfamily members CD40, Fas and TRAILR2 modulate CD40 signalling.
Smulski Cristian R, Decossas Marion, Chekkat Neila, Beyrath Julien, Willen Laure, Guichard Gilles, Lorenzetti Raquel, Rizzi Marta, Eibel Hermann, Schneider Pascal, Fournel Sylvie (2017), Hetero-oligomerization between the TNF receptor superfamily members CD40, Fas and TRAILR2 modulate CD40 signalling., in Cell death & disease, 8(2), 2601-2601.
Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases.
Samy Eileen, Wax Stephen, Huard Bertrand, Hess Henry, Schneider Pascal (2017), Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases., in International reviews of immunology, 36(1), 3-19.
Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.
del Rio Maria-Luisa, Fernandez-Renedo Carlos, Chaloin Olivier, Scheu Stefanie, Pfeffer Klaus, Shintani Yasushi, Perez-Simon Jose-Antonio, Schneider Pascal, Rodriguez-Barbosa Jose-Ignacio (2016), Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells., in mAbs, 8(3), 478-90.
Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration.
Alvarez Alvaro, Lagos-Cabré Raúl, Kong Milene, Cárdenas Areli, Burgos-Bravo Francesca, Schneider Pascal, Quest Andrew F G, Leyton Lisette (2016), Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration., in Biochimica et biophysica acta, 1863(9), 2175-88.
Antibodies That Block or Activate Mouse B Cell Activating Factor of the Tumor Necrosis Factor (TNF) Family (BAFF), Respectively, Induce B Cell Depletion or B Cell Hyperplasia.
Kowalczyk-Quintas Christine, Schuepbach-Mallepell Sonia, Vigolo Michele, Willen Laure, Tardivel Aubry, Smulski Cristian R, Zheng Timothy S, Gommerman Jennifer, Hess Henry, Gottenberg Jacques-Eric, Mackay Fabienne, Donzé Olivier, Schneider Pascal (2016), Antibodies That Block or Activate Mouse B Cell Activating Factor of the Tumor Necrosis Factor (TNF) Family (BAFF), Respectively, Induce B Cell Depletion or B Cell Hyperplasia., in The Journal of biological chemistry, 291(38), 19826-34.
Characterization and application of two RANK-specific antibodies with different biological activities.
Chypre Mélanie, Seaman Jonathan, Cordeiro Olga G, Willen Laure, Knoop Kathryn A, Buchanan Andrew, Sainson Richard C A, Williams Ifor R, Yagita Hideo, Schneider Pascal, Mueller Christopher G (2016), Characterization and application of two RANK-specific antibodies with different biological activities., in Immunology letters, 171, 5-14.
Data for the crystal structure of APRIL-BAFF-BAFF heterotrimer.
Maskos Klaus, Lammens Alfred, Tan Seng-Lai, Hess Henry, Palinsky Wolf, Schneider Pascal, Jiang Xuliang (2016), Data for the crystal structure of APRIL-BAFF-BAFF heterotrimer., in Data in brief, 6, 438-44.
Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis.
Grosjean Frédéric, Nasi Sonia, Schneider Pascal, Chobaz Véronique, Liu Alexandra, Mordasini Vanessa, Moullec Kristell, Vezzoni Paolo, Lavanchy Christine, Busso Nathalie, Acha-Orbea Hans, Ehirchiou Driss (2015), Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis., in PloS one, 10(8), 0133917-0133917.
Ectodysplasin/NF-κB Promotes Mammary Cell Fate via Wnt/β-catenin Pathway.
Voutilainen Maria, Lindfors Päivi H, Trela Ewelina, Lönnblad Darielle, Shirokova Vera, Elo Teresa, Rysti Elisa, Schmidt-Ullrich Ruth, Schneider Pascal, Mikkola Marja L (2015), Ectodysplasin/NF-κB Promotes Mammary Cell Fate via Wnt/β-catenin Pathway., in PLoS genetics, 11(11), 1005676-1005676.
Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.
Woess C, Tuzlak S, Labi V, Drach M, Bertele D, Schneider P, Villunger A (2015), Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice., in Cell death and differentiation, 22(9), 1477-88.
Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival.
Johnston Amelia J, Murphy Kate T, Jenkinson Laura, Laine David, Emmrich Kerstin, Faou Pierre, Weston Ross, Jayatilleke Krishnath M, Schloegel Jessie, Talbo Gert, Casey Joanne L, Levina Vita, Wong W Wei-Lynn, Dillon Helen, Sahay Tushar, Hoogenraad Joan, Anderton Holly, Hall Cathrine, Schneider Pascal, Tanzer Maria, Foley Michael, Scott Andrew M, Gregorevic Paul, Liu Spring Yingchun, Burkly Linda C, Lynch Gordon S, Silke John, Hoogenraad Nicholas J (2015), Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival., in Cell, 162(6), 1365-78.
Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.
Wild J, Schmiedel B J, Maurer A, Raab S, Prokop L, Stevanović S, Dörfel D, Schneider P, Salih H R (2015), Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis., in Leukemia, 29(8), 1676-83.
Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.
Schuepbach-Mallepell Sonia, Das Dolon, Willen Laure, Vigolo Michele, Tardivel Aubry, Lebon Luc, Kowalczyk-Quintas Christine, Nys Josquin, Smulski Cristian, Zheng Timothy S, Maskos Klaus, Lammens Alfred, Jiang Xuliang, Hess Henry, Tan Seng-Lai, Schneider Pascal (2015), Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties., in The Journal of biological chemistry, 290(26), 16330-42.
Epithelial NAIPs protect against colonic tumorigenesis.
Allam Ramanjaneyulu, Maillard Michel H, Tardivel Aubry, Chennupati Vijaykumar, Bega Hristina, Yu Chi Wang, Velin Dominique, Schneider Pascal, Maslowski Kendle M (2015), Epithelial NAIPs protect against colonic tumorigenesis., in The Journal of experimental medicine, 212(3), 369-83.
Pharmacological stimulation of Edar signaling in the adult enhances sebaceous gland size and function.
Kowalczyk-Quintas Christine, Schuepbach-Mallepell Sonia, Willen Laure, Smith Terry K, Huttner Kenneth, Kirby Neil, Headon Denis J, Schneider Pascal (2015), Pharmacological stimulation of Edar signaling in the adult enhances sebaceous gland size and function., in The Journal of investigative dermatology, 135(2), 359-368.
B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.
François Antoine, Gombault Aurélie, Villeret Bérengère, Alsaleh Ghada, Fanny Manoussa, Gasse Paméla, Adam Sylvain Marchand, Crestani Bruno, Sibilia Jean, Schneider Pascal, Bahram Seiamak, Quesniaux Valérie, Ryffel Bernhard, Wachsmann Dominique, Gottenberg Jacques-Eric, Couillin Isabelle (2015), B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis., in Journal of autoimmunity, 56, 1-11.

Collaboration

Group / person Country
Types of collaboration
Dr Bertrand Huard, Université de Grenoble, France France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Rena D'Souza, University of Utah, Salt Lake City United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr Neil Kirby, EdimerPharma, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Dr Henry Hess, Merck-Serono, Darmstadt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Dr Denis Headon, Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Hermann Eibel, University of Freiburg, Germany Germany (Europe)
- Publication
Dr Fabienne Mackay, Garvan Insitute for Medical Research, Sydney Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
Dr Margaret Casal, University of Pennsylvania, Philadelphia United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr Holm Schneider, University of Erlangen, Germany Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr Olivier Gaide, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
16th TNF Superfamily Meeting 2017 Talk given at a conference Cure of a genetic disability: the winning pair of neonatal Fc receptor and intra-amniotic delivery of EDAR agonists in ectodysplasin A1-deficient mice and humans 17.04.2017 Singapore, Singapore Schneider Pascal;
ZTZ opening symposium, University of Freiburg (D) Talk given at a conference The B cell survival cytokines BAFF and APRIL: Mutants uncoupling receptor binding from biological effects reveal how BAFF signals 16.09.2016 Freiburg, Germany Schneider Pascal;
TMD Meeting, Helsinki (Finlande) Talk given at a conference Pharmacological manipulation of the EDA-EDAR pathway 18.06.2016 Porvoo, Finland Schneider Pascal;
Gordon Research Conference, Teeth and bones, Galveston (USA) Talk given at a conference Pharmacological manipulation of the EDA-EDAR pathway 12.02.2016 Galveston, United States of America Schneider Pascal;
International TNF Meeting, Ghent (Belgique) Talk given at a conference Mutants uncoupling receptor binding from biological effects reveal how the TNF family ligand BAFF/BLyS signals 17.05.2015 Ghent, Belgium Schneider Pascal;


Associated projects

Number Title Start Funding scheme
138065 TNF family ligands BAFF, APRIL and EDA 01.10.2011 Project funding (Div. I-III)
67927 Function of the TNF family ligands EDA, BAFF and APRIL 01.10.2002 Project funding (Div. I-III)
109443 Function of the TNF family ligands BAFF, APRIL and EDA 01.10.2005 Project funding (Div. I-III)
176256 TNF family ligands BAFF, APRIL and EDA 01.11.2017 Project funding (Div. I-III)
138065 TNF family ligands BAFF, APRIL and EDA 01.10.2011 Project funding (Div. I-III)

Abstract

Ectodysplasin A (EDA), and B cell activation factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), are structurally related TNF family ligands with different functions. EDA is active during development and participates to the formation of hair, teeth and a variety of glands. Inactivating mutations in the EDA gene are causative of X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare congenital disorder with severe, and sometimes life-threatening effects on thermoregulation, resistance to airways infections, and skin and tooth integrity. We have developed a protein replacement therapy for the treatment of XLHED that is presently tested in clinical trials, and have recently identified in mice that adult sebaceous glands respond to EDA receptor (EDAR) agonists, opening the way to potential applications in patients affected with diseases other than XLHED. In order to better understand the biology of EDA and to extend or improve existing treatment options, we will i) characterize the in vivo role of the interaction of EDA with proteoglycans that has remained elusive so far; ii) measure circulating EDA levels to identify conditions with deregulated EDA expression, and also to help diagnose XLHED; iii) refine administration procedures of EDAR agonists to fetuses, to increase the probability of treatment success; and iv) characterize glands that can respond to EDAR modulation in adults. BAFF and APRIL are central cytokines for the survival, maturation, homeostasis, and differentiation of B cells in the periphery. They are pharmacological targets for the treatment of systemic lupus erythematous (SLE), an autoimmune condition characterized, among others, by elevated autoantibody levels. BAFF and APRIL act through activation of three distinct receptors. Although crystal structures display in great details how ligands interact with receptors, we believe that the molecular mechanisms by which receptors are activated is not yet fully understood. For example, we find that BAFF and APRIL receptors can directly interact with each other, a property that has not been revealed in crystal structures. We will map the relevant portions of the receptors involved in receptor - receptor interactions, and explore the potential impact of these interactions on signaling. Also, we have identified a portion of BAFF that is entirely dispensable for proper ligand folding and receptor binding, but that is required for the activity of BAFF in vivo. The characterization of this finding will significantly alter current models of ligand-induced receptor activation. Finally, a detailed investigation of the receptor-ligand pairs required for the survival of long-lived plasma cells will provide a comprehensive view of unique and redundant interactions in this important biological process. Taken together, the research planned in this application will address fundamental issues of signal initiation mediated by BAFF, APRIL and EDA, and yield data with immediate implications to guide development or improvement of clinical treatments.
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