Project

Back to overview

TNF family ligands BAFF, APRIL and EDA

English title TNF family ligands BAFF, APRIL and EDA
Applicant Schneider Pascal
Number 176256
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 01.11.2017 - 31.10.2021
Approved amount 800'000.00
Show all

All Disciplines (4)

Discipline
Biochemistry
Immunology, Immunopathology
Molecular Biology
Embryology, Developmental Biology

Keywords (8)

B cells; immunity; antibodies; immunodeficiency; signaling; protein structure; ectodermal dysplasia; therapy

Lay Summary (French)

Lead
Les ligands de la famille du TNF contribuent à la fonction du système immunitaire, comme BAFF et APRIL qui font survivre les lymphocytes B et les cellules sécrétrices d’anticorps qui en dérivent. EDA est une exception : il est actif lors du développement des phanères (poils, dents et diverses glandes). Certains aspects de la fonction et de l’exploitation thérapeutique de ces ligands restent inexplorés. Le projet apporte une contribution à ces deux aspects.
Lay summary

Contenu et objectifs du travail de recherche

Comme les cellules B dépendent de BAFF pour leur survie, BAFF, APRIL et leurs récepteurs sont impliqués tant dans l’autoimmunité (excès) que dans l’immunodéficience (déficit). Pour mieux comprendre comment BAFF active son récepteur, nous poursuivrons notre étude qui démontre la possibilité de dissocier la liaison de BAFF au récepteur de son activation. L’étude des formes oligomériques de BAFF, d’APRIL et de leurs hétéromères sera donc au cœur de ce projet.

 

L’inactivation génétique d’EDA cause une dysplasie ectodermique (syndrome de Christ-Siemens-Touraine (CST)). Le projet étudie des questions fondamentales sur la physiologie et la structure d’EDA ainsi que sur le mécanisme d’action d’une thérapie de remplacement protéinique initialement développée dans notre groupe et récemment testée chez trois fétus avec le syndrome CST, ce qui a restauré la sudation chez ces patients après la naissance. L’une des questions centrales sera de déterminer comment le médicament administré dans le liquide amniotique, c’est-à-dire à l’extérieur du fœtus, peut agir sur les tissus cibles.

 

Contexte scientifique et social du projet de recherche

Les aspects fondamentaux de cette recherche permettront 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 et l’extension de thérapies pour des pathologies en manque de traitements, comme le syndrome de Christ-Siemens-Touraine.

Direct link to Lay Summary Last update: 30.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Novel strategies for expansion of tooth epithelial stem cells and ameloblast generation
Binder Martin, Biggs Leah C., Kronenberg Mark S., Schneider Pascal, Thesleff Irma, Balic Anamaria (2020), Novel strategies for expansion of tooth epithelial stem cells and ameloblast generation, in Scientific Reports, 10(1), 4963-4963.
The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens
Rodriguez-Barbosa Jose-Ignacio, Schneider Pascal, Graca Luis, Bühler Leo, Perez-Simon Jose-Antonio, del Rio Maria-Luisa (2020), The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens, in International Journal of Molecular Sciences, 21(9), 3347-3347.
No interactions between heparin and atacicept, an antagonist of B cell survival cytokines
Kowalczyk‐Quintas Christine, Willen Daniela, Willen Laure, Golob Michaela, Schuepbach‐Mallepell Sonia, Peter Benjamin, Eslami Mahya, Vigolo Michele, Broly Hervé, Samy Eileen, Yalkinoglu Özkan, Schneider Pascal (2019), No interactions between heparin and atacicept, an antagonist of B cell survival cytokines, in British Journal of Pharmacology, 176(20), 4019-4033.
Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model
Margolis Carol A., Schneider Pascal, Huttner Kenneth, Kirby Neil, Houser Timothy P., Wildman Lee, Grove Gary L., Schneider Holm, Casal Margret L. (2019), Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model, in Journal of Pharmacology and Experimental Therapeutics, 370(3), 806-813.
HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT
Rodriguez-Barbosa Jose Ignacio, Schneider Pascal, Weigert Andreas, Lee Kyung-Mi, Kim Tae-Jin, Perez-Simon Jose-Antonio, del Rio Maria-Luisa (2019), HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT, in Cellular & Molecular Immunology, 16(7), 679-682.
TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes
Staniek Julian, Lorenzetti Raquel, Heller Bianca, Janowska Iga, Schneider Pascal, Unger Susanne, Warnatz Klaus, Seidl Maximilian, Venhoff Nils, Thiel Jens, Smulski Cristian Roberto, Rizzi Marta (2019), TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes, in Frontiers in Immunology, 10, 951.
Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia
del-Pozo Jorge, MacIntyre Neil, Azar Ali, Headon Denis, Schneider Pascal, Cheeseman Michael (2019), Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia, in Disease Models & Mechanisms, 12(4), dmm037804-dmm037804.
Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL
Clar Kim, Hinterleitner Clemens, Schneider Pascal, Salih Helmut, Maurer Stefanie (2019), Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL, in Cancers, 11(3), 277-277.
Feather arrays are patterned by interacting signalling and cell density waves
Ho William K. W., Freem Lucy, Zhao Debiao, Painter Kevin J., Woolley Thomas E., Gaffney Eamonn A., McGrew Michael J., Tzika Athanasia, Milinkovitch Michel C., Schneider Pascal, Drusko Armin, Matthäus Franziska, Glover James D., Wells Kirsty L., Johansson Jeanette A., Davey Megan G., Sang Helen M., Clinton Michael, Headon Denis J. (2019), Feather arrays are patterned by interacting signalling and cell density waves, in PLOS Biology, 17(2), e3000132-e3000132.
Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning
Sadier Alexa, Twarogowska Monika, Steklikova Klara, Hayden Luke, Lambert Anne, Schneider Pascal, Laudet Vincent, Hovorakova Maria, Calvez Vincent, Pantalacci Sophie (2019), Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning, in PLOS Biology, 17(2), e3000064-e3000064.
A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis
Baert Laurie, Benkhoucha Mahdia, Popa Natalia, Ahmed Mashal C., Manfroi Benoit, Boutonnat Jean, Sturm Nathalie, Raguenez Gilda, Tessier Marine, Casez Olivier, Marignier Romain, Ahmadi Mitra, Broisat Alexis, Ghezzi Catherine, Rivat Cyril, Sonrier Corinne, Hahne Michael, Baeten Dominique, Vives Romain R., Lortat‐Jacob Hugues, Marche Patrice N., Schneider Pascal, Lassmann Hans P., Boucraut Jose, et al. (2019), A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis, in Annals of Neurology, ana.25415-ana.25415.
A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors
Vigolo Michele, Chambers Melissa G., Willen Laure, Chevalley Dehlia, Maskos Klaus, Lammens Alfred, Tardivel Aubry, Das Dolon, Kowalczyk-Quintas Christine, Schuepbach-Mallepell Sonia, Smulski Cristian R., Eslami Mahya, Rolink Antonius, Hummler Edith, Samy Eileen, Fomekong Nanfack Yves, Mackay Fabienne, Liao Maofu, Hess Henry, Jiang Xuliang, Schneider Pascal (2018), A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors, in Nature Communications, 9(1), 1199-1199.
CART cells are prone to Fas- and DR5-mediated cell death
Tschumi Benjamin O., Dumauthioz Nina, Marti Bastien, Zhang Lianjun, Schneider Pascal, Mach Jean-Pierre, Romero Pedro, Donda Alena (2018), CART cells are prone to Fas- and DR5-mediated cell death, in Journal for ImmunoTherapy of Cancer, 6(1), 71-71.
B Cell–Activating Factor Neutralization Aggravates Atherosclerosis
Tsiantoulas Dimitrios, Sage Andrew P., Göderle Laura, Ozsvar-Kozma Maria, Murphy Deirdre, Porsch Florentina, Pasterkamp Gerard, Menche Jörg, Schneider Pascal, Mallat Ziad, Binder Christoph J. (2018), B Cell–Activating Factor Neutralization Aggravates Atherosclerosis, in Circulation, 138(20), 2263-2273.
Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy
Wahlbuhl Mandy, Schuepbach-Mallepell Sonia, Kowalczyk-Quintas Christine, Dick Angela, Fahlbusch Fabian B., Schneider Pascal, Schneider Holm (2018), Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy, in Journal of Mammary Gland Biology and Neoplasia, 23(3), 125-138.
Antibiotic treatment–induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia
Robak Oliver H., Heimesaat Markus M., Kruglov Andrey A., Prepens Sandra, Ninnemann Justus, Gutbier Birgitt, Reppe Katrin, Hochrein Hubertus, Suter Mark, Kirschning Carsten J., Marathe Veena, Buer Jan, Hornef Mathias W., Schnare Markus, Schneider Pascal, Witzenrath Martin, Bereswill Stefan, Steinhoff Ulrich, Suttorp Norbert, Sander Leif E., Chaput Catherine, Opitz Bastian (2018), Antibiotic treatment–induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia, in Journal of Clinical Investigation, 128(8), 3535-3545.
B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD)
Bruzzì Stefania, Sutti Salvatore, Giudici Gabriele, Burlone Michela E., Ramavath Naresh Naik, Toscani Alberto, Bozzola Cristina, Schneider Pascal, Morello Elisabetta, Parola Maurizio, Pirisi Mario, Albano Emanuele (2018), B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD), in Free Radical Biology and Medicine, 124, 249-259.
Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation
Rodriguez-Barbosa J.I., Ferreras M.C., Buhler L., Jones N.D., Schneider P., Perez-Simon J.A., del Rio M.L. (2018), Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation, in mAbs, 1-15.
Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis
Huang Hsin-Ying, Rivas-Caicedo Ana, Renevey François, Cannelle Hélène, Peranzoni Elisa, Scarpellino Leonardo, Hardie Debbie L., Pommier Arnaud, Schaeuble Karin, Favre Stéphanie, Vogt Tobias K., Arenzana-Seisdedos Fernando, Schneider Pascal, Buckley Christopher D., Donnadieu Emmanuel, Luther Sanjiv A. (2018), Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis, in Proceedings of the National Academy of Sciences, 115(29), E6826-E6835.
Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia
Schneider Holm, Faschingbauer Florian, Schuepbach-Mallepell Sonia, Körber Iris, Wohlfart Sigrun, Dick Angela, Wahlbuhl Mandy, Kowalczyk-Quintas Christine, Vigolo Michele, Kirby Neil, Tannert Corinna, Rompel Oliver, Rascher Wolfgang, Beckmann Matthias W., Schneider Pascal (2018), Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia, in New England Journal of Medicine, 378(17), 1604-1610.
Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation
Chennupati Vijaykumar, Veiga Diogo F.T., Maslowski Kendle M., Andina Nicola, Tardivel Aubry, Yu Eric Chi-Wang, Stilinovic Martina, Simillion Cedric, Duchosal Michel A., Quadroni Manfredo, Roberts Irene, Sankaran Vijay G., MacDonald H. Robson, Fasel Nicolas, Angelillo-Scherrer Anne, Schneider Pascal, Hoang Trang, Allam Ramanjaneyulu (2018), Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation, in Journal of Clinical Investigation, 128(4), 1597-1614.
The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia
Nuebling Tina, Schumacher Carla Emilia, Hofmann Martin, Hagelstein Ilona, Schmiedel Benjamin Joachim, Maurer Stefanie, Federmann Birgit, Rothfelder Kathrin, Roerden Malte, Dörfel Daniela, Schneider Pascal, Jung Gundram, Salih Helmut Rainer (2018), The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia, in Cancer Immunology Research, 6(2), 209-221.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
IADR Presidential Symposium at the IADR/AADR/CADR General Session Talk given at a conference Prenatal correction of ectodermal dysplasia in human twin boys 19.06.2019 Vancouver, Canada Schneider Pascal;
17th International TNF conference Talk given at a conference Biochemical and clinical aspects of the TNF family ligand Ectodysplasin A (EDA) 03.06.2019 Asilomar, CA, United States of America Schneider Pascal;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Therapie bereits vor der Geburt SFR German-speaking Switzerland 2018
Media relations: print media, online media Twins treated for genetic disorder in the womb CNN International 2018
Media relations: radio, television Un traitement inédit pour une maladie rare jusqu’alors incurable rts la-1ere Western Switzerland 2018

Associated projects

Number Title Start Funding scheme
156961 TNF family ligands BAFF, APRIL and EDA 01.11.2014 Project funding (Div. I-III)

Abstract

Members of the TNF family are trimeric ligands that signal by clustering specific receptors. Almost all TNF family members are involved in the establishment, maintenance or effector functions of the immune system. For example, B cell activation factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are important survival and fitness factors for peripheral B cells. Ectodysplasin A (EDA), a striking exception to the rule, instead controls formation of skin-derived appendages during embryonic development. Genetic EDA inactivation causes X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized, among others, by hypodontia, recurrent airways infections and a severe inability to sweat resulting in life-threatening heat-intolerance. A protein replacement therapy initially designed in our laboratory was assayed for three babies in a trial to cure. In these case studies, sweating ability was restored by administration of Fc-EDA outside fetuses, in the amniotic fluid. How Fc-EDA administered by different routes reaches and acts on relevant tissues will be defined in this application. We will also tackle unaddressed fundamental questions about EDA physiology and structure: its interaction with proteoglycans (which turns out to be gripping!), the structure-function relationship of the protein as a whole, its role in shaping adult mammary glands, and the origin and function of tissue versus circulating EDA. The creation of a reporter and conditional Eda knock-out mouse will help answer some of these questions. Cell survival in multi-cellular organisms is a tightly controlled process, and B cells that depend on several different survival factors or signals are no exception. BAFF, APRIL and heteromers thereof participate to survival, homeostasis and maturation of peripheral B cells at different stages of differentiation through three distinct receptors. On the one hand, elevated BAFF levels can promote auto-reactive B cells and autoimmunity, and anti-BAFF therapy is approved for treatment of systemic lupus erythematosus. One the other hand, mutations in receptors for BAFF or APRIL are associated with hypogammaglobulinemia and immunodeficiency. In order to better understand steps of receptor activation, we will build on our strong evidence that events of receptor binding and receptor activation can be dissociated. Thus, we will study the physiological roles of small and large BAFF oligomers, explore an intrinsic (proteoglycan-independent) oligomerization property of APRIL, develop pharmacological agents to study the function of BAFF and APRIL heteromers, address the structural and functional impact of post-translational modifications of BAFF and APRIL and explore the possibility that a ligand-independent signaling ability of TACI, one of the APRIL and BAFF receptors, could be disrupted in patients with common variable immunodeficiency.These studies will provide fundamental information on the structure, physiology and mechanism of action of BAFF, APRIL and EDA and help to further develop a successful therapy for ectodermal dysplasia.
-