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TNF family ligands BAFF, APRIL and EDA

English title TNF family ligands BAFF, APRIL and EDA
Applicant Schneider Pascal
Number 138065
Funding scheme Project funding (Div. I-III)
Research institution Centre Integratif de Genomique Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.10.2011 - 30.09.2014
Approved amount 438'000.00
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All Disciplines (4)

Discipline
Biochemistry
Molecular Biology
Embryology, Developmental Biology
Immunology, Immunopathology

Keywords (5)

B cells; TNF; reverse signaling; therapy; ectodermal dysplasia

Lay Summary (English)

Lead
Lay summary

TNF family members BAFF, APRIL and EDA:

BAFF/BLyS and APRIL are important for survival and development of peripheral B lymphocytes at various stages of differentiation. Ectodysplasin A (EDA) is essential for proper development of various ectodermal skin appendages, such as hair teeth and sweat glands. Despite their different functions, BAFF, APRIL and EDA are related members of the TNF family representing valuable therapeutic targets for the treatment of several diseases.

In animal models of EDA-deficiency, a protein replacement approach was successful for long-term reversion of symptoms, provided that treatment was given at the time of normal development of EDA-dependent structures. Agonist anti-EDAR antibodies with potent in vivo activity were recently developed that open new perspectives for long-term treatment experiments in various animal models and possibly human. A recombinant form of EDA is in preclinical development, with phase I clinical trials planned to start within a year. With these reagents, there is a real hope to treat X-linked hypohidrotic ectodermal dysplasia (XL-HED) in human, a severe condition characterized, among other, by episodes of hyperthermia because of a lack of sweat glands, recurrent airways infections because mucous secreting glands function abnormally, and by severe teeth malformation.

Using a pharmacological system in which we can control the dose, initiation time and termination time of EDA receptor (EDAR) signaling, we want to characterize precisely the dose and timing of administration that are required for development of a variety of EDA-dependent features in EDA-deficient mice. We also plan to determine whether tooth, hair and sweat gland development differ in their requirements for EDAR signals, and identify the molecular reason underlying loss of EDA-responsiveness after a certain time period. Another major endeavor is the identification of biomarkers of treatment activity. We will also address the physiological relevance of the observed interaction of EDA with proteoglycans.

The biology of BAFF and APRIL is characterized by its complexity: it involves numerous forms of BAFF and APRIL, proteoglycans and three receptors, BCMA, TACI and BAFFR. BAFF is processed at a furin consensus cleavage site. Once processed, it can exist as soluble 3-mer or 60-mer. BAFF 60-mer, but not BAFF 3-mer can trigger signaling through TACI in primary B cells in vitro. We want to determine the physiologic function of large BAFF oligomers by analyzing the phenotype of knock-in mice in which BAFF cannot form 60-mers. We also will assess agonist and antagonist activity of BAFF-APRIL heteromers of defined stoechiometry in vitro and in vivo.
Clinical trials with BAFF antagonists result in B cell depletion and decreased circulating antibody levels, as expected for blockade of a B cell survival factor. However, these trials also revealed unexpected effects, such as a transient increase of B cell numbers and exacerbation of symptoms in patients with multiple sclerosis. We will explore several hypotheses that could explain such an effect: removal of a TACI-mediated inhibition, depletion of IL10-producing regulatory B cells, and/or activation of myeloid cells through reverse BAFF-signaling.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Astrocte-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 (2017), Astrocte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway, in BBA Molecular Cell Research, 1864, 243-254.
BAFF- and TACI-dependent processing of BAFFR by ADAM proteases regulates the survival of B cells
Smulski C Kury P Seidel LM Staiger HS Edinger AK Willen L Seidl M Hess H Salzer U Rolink AG (2017), BAFF- and TACI-dependent processing of BAFFR by ADAM proteases regulates the survival of B cells, in Cell Reports , 18, 2189-2202.
CXCL-8/IL-8 produced by diffuse large B-cell lymphomas recruits neutrophils expressing a proliferation inducing ligand APRIL
Manfroi B McKey T Mayol JF Tabruyn S Moret S Villiers C Righini C Dyer M Callanan M Schne (2017), CXCL-8/IL-8 produced by diffuse large B-cell lymphomas recruits neutrophils expressing a proliferation inducing ligand APRIL, in Cancer Research, 77, 1097-1107.
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 H (2017), Ectodysplasin A in biological fluids and diagnosis of ectodermal dysplasia, in J. Dental Research , 96, 217-224.
Hetero-oligomerization between the TNF receptor superfamily members CD40, FAS and TRAIL-R2 modulate CD40 signalling
Smulski C Decossas M Chekkat N Beyrath J Willen L Guichard G Lorenzetti R Rizzi M Eibel H S (2017), Hetero-oligomerization between the TNF receptor superfamily members CD40, FAS and TRAIL-R2 modulate CD40 signalling, in Cell Death Disease , e2601 , e2601 -e2601.
N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced cell death
Dufour F Rattier T Shirley S Pacarda G Constantinescu AA Morlé A Zakaria AB Marcion G Causse (2017), N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced cell death, in Cell Death and Diff, 24, 500-510.
Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases
Samy E Wax S Huard B Hess H Schneider P (2017), Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases, in International Reviews of Immunology , 36, 3-19.
Antibodies that block or activate mouse B cell activating factor of the TNF family respectively induce B cell depletion or B cell hyperplasia
Kowalczyk-Quintas C Schuepbach-Mallepell S Vigolo M Willen L Tardivel A Smulski CR Zheng TS G (2016), Antibodies that block or activate mouse B cell activating factor of the TNF family respectively induce B cell depletion or B cell hyperplasia, in J. Biol. Chem, 291, 19826-19834.
Characterization and application of two RANK-specific antibodies with different biological activities
Chypre M Seaman J Cordeiro OG Willen L Knoop KA Buchanan A Sainson RCA Williams IR Yagita H (2016), Characterization and application of two RANK-specific antibodies with different biological activities, in Immunology Letters , 171, 5-14.
Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells
Del Rio ML Fernandez-Renedo C Chaloin O Scheu S Pfeffer K Shintani Y Perez-Simon JA Schneider (2016), Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells, in mAbs , 8, 478-490.
Integrin-mediated transactivation of P2X7 receptors via hemichannel opening-dependent ATP release stimulates astrocyte migration
Alvarez A Lagos-Cabré R Kong M Cárdenas A Burgos-Bravo F Schneider P Quest AF Leyton L (2016), Integrin-mediated transactivation of P2X7 receptors via hemichannel opening-dependent ATP release stimulates astrocyte migration, in BBA Molecular Cell Research , 1863, 2175-2188.
BAFF is central to bleomycin and IL17-mediated experimental pulmonary fibrosis
Francois A Villeret B Gombault A Alsaleh G Gasse P Marchand Adam S Sibilia J Schneider P Que (2015), BAFF is central to bleomycin and IL17-mediated experimental pulmonary fibrosis, in J. Autoimmunity , 56, 1-11.
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 Bertele D Mathias Drach M 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 Diff., 22, 1477-1488.
Data for the crystal structure of APRIL-BAFF-BAFF heterotrimer
Maskos K Lammens A Tan SL Hess H Palinsky W Schneider P Jiang X (2015), Data for the crystal structure of APRIL-BAFF-BAFF heterotrimer, in Data Brief , 6, 438-444.
Dendritic cells cause bone lesions in a new mouse model of histiocytosis.
Grosjean F Nasi S Schneider P Chobaz V Lui A Mordasini V Moulek K Vezzoni P Lavanchy C Buss (2015), Dendritic cells cause bone lesions in a new mouse model of histiocytosis., in PLoS One, 10:e0133917, 10:e013391-10:e013391.
Ectodysplasin/NF-kB promotes mammary cell fate via Wnt/ß-catenin pathway
Voutilainen M Lidfors PH Trela E Lönnblad D Shirokova V Elo T Rysti E Schmidt-Ullrich R Schn (2015), Ectodysplasin/NF-kB promotes mammary cell fate via Wnt/ß-catenin pathway, in PLOS Genetics , 11.e1005676, 11.e100567-11.e100567.
Epithelial NAIPs protect against colonic tumorigenesis
Allam R Parpanov R Maillard MH Chennupati V Tardivel A Bega H Yu CW Velin D Schneider P Ma (2015), Epithelial NAIPs protect against colonic tumorigenesis, in J. Exp. Med., 212, 369-383.
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 Maurer A Raab A Prokop L Stevanovic S Dörfel D Schneider P and Salih H (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, 1676-1683.
Stoichiometry of heteromeric BAFF and APRIL cytokines dictate their receptor-binding and signalling properties.
Schuepbach-Mallepell S Das D Willen L Vigolo M Tardivel A Lebon L Kowalczyk-Quintas C Nys J (2015), Stoichiometry of heteromeric BAFF and APRIL cytokines dictate their receptor-binding and signalling properties., in J. Biol. Chem, 290, 16330-16342.
Targeting of Fn14 prevents cachexia
Johnston AJ Murphy KT Jenkinson L Laine D Emmrich K Faou P Weston R Jayatilleke KM Schloegel (2015), Targeting of Fn14 prevents cachexia, in Cell, 162, 1365-1378.
A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency.
Pieper Kathrin, Rizzi Marta, Speletas Matthaios, Smulski Cristian R, Sic Heiko, Kraus Helene, Salzer Ulrich, Fiala Gina J, Schamel Wolfgang W, Lougaris Vassilios, Plebani Alessandro, Hammarstrom Lennart, Recher Mike, Germenis Anastasios E, Grimbacher Bodo, Warnatz Klaus, Rolink Antonius G, Schneider Pascal, Notarangelo Luigi D, Eibel Hermann (2014), A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency., in The Journal of allergy and clinical immunology, 133(4), 1222-5.
Ectodysplasin A (EDA) - EDA receptor signalling and its pharmacological modulation.
Kowalczyk-Quintas Christine, Schneider Pascal (2014), Ectodysplasin A (EDA) - EDA receptor signalling and its pharmacological modulation., in Cytokine & growth factor reviews, 25(2), 195-203.
Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia.
Kowalczyk-Quintas Christine, Willen Laure, Dang Anh Thu, Sarrasin Heidi, Tardivel Aubry, Hermes Katharina, Schneider Holm, Gaide Olivier, Donzé Olivier, Kirby Neil, Headon Denis J, Schneider Pascal (2014), Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia., in The Journal of biological chemistry, 289(7), 4273-85.
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 (2014), Pharmacological Stimulation of Edar Signaling in the Adult Enhances Sebaceous Gland Size and Function., in The Journal of investigative dermatology, xx-yy.
Prenatal Therapy in Developmental Disorders: Drug Targeting via Intra-Amniotic Injection to Treat X-Linked Hypohidrotic Ectodermal Dysplasia.
Hermes Katharina, Schneider Pascal, Krieg Peter, Dang AnhThu, Huttner Kenneth, Schneider Holm (2014), Prenatal Therapy in Developmental Disorders: Drug Targeting via Intra-Amniotic Injection to Treat X-Linked Hypohidrotic Ectodermal Dysplasia., in The Journal of investigative dermatology, 134(12), 2985-7.
Therapeutic Blockade of LIGHT Interaction With Herpesvirus Entry Mediator and Lymphotoxin β Receptor Attenuates In Vivo Cytotoxic Allogeneic Responses.
Del Rio Maria-Luisa, Fernandez-Renedo Carlos, Scheu Stefanie, Pfeffer Klaus, Shintani Yasushi, Kronenberg Mitchell, Chaloin Olivier, Schneider Pascal, Rodriguez-Barbosa Jose-Ignacio (2014), Therapeutic Blockade of LIGHT Interaction With Herpesvirus Entry Mediator and Lymphotoxin β Receptor Attenuates In Vivo Cytotoxic Allogeneic Responses., in Transplantation, xx-yy.
Tools and techniques to study ligand-receptor interactions and receptor activation by TNF superfamily members.
Schneider Pascal, Willen Laure, Smulski Cristian R (2014), Tools and techniques to study ligand-receptor interactions and receptor activation by TNF superfamily members., in Methods in enzymology, 545, 103-25.
Cysteine-rich domain 1 of CD40 mediates receptor self-assembly.
Smulski Cristian R, Beyrath Julien, Decossas Marion, Chekkat Neila, Wolff Philippe, Estieu-Gionnet Karine, Guichard Gilles, Speiser Daniel, Schneider Pascal, Fournel Sylvie (2013), Cysteine-rich domain 1 of CD40 mediates receptor self-assembly., in The Journal of biological chemistry, 288(15), 10914-22.
Effects of fructose-containing caloric sweeteners on resting energy expenditure and energy efficiency: a review of human trials.
Tappy Luc, Egli Leonie, Lecoultre Virgile, Schneider Pascal (2013), Effects of fructose-containing caloric sweeteners on resting energy expenditure and energy efficiency: a review of human trials., in Nutrition & metabolism, 10(1), 54-54.
Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses.
Smith Wendell, Tomasec Peter, Aicheler Rebecca, Loewendorf Andrea, Nemčovičová Ivana, Wang Eddie C Y, Stanton Richard J, Macauley Matt, Norris Paula, Willen Laure, Ruckova Eva, Nomoto Akio, Schneider Pascal, Hahn Gabriele, Zajonc Dirk M, Ware Carl F, Wilkinson Gavin W G, Benedict Chris A (2013), Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses., in Cell host & microbe, 13(3), 324-35.
LIGHT/HVEM/LTβR interaction as a target for the modulation of the allogeneic immune response in transplantation.
del Rio M-L, Schneider P, Fernandez-Renedo C, Perez-Simon J-A, Rodriguez-Barbosa J-I (2013), LIGHT/HVEM/LTβR interaction as a target for the modulation of the allogeneic immune response in transplantation., in American journal of transplantation : official journal of the American Society of Transplantation an, 13(3), 541-51.
No evidence that soluble TACI induces signalling via membrane-expressed BAFF and APRIL in myeloid cells.
Nys Josquin, Smulski Cristian R, Tardivel Aubry, Willen Laure, Kowalczyk Christine, Donzé Olivier, Huard Bertrand, Hess Henry, Schneider Pascal (2013), No evidence that soluble TACI induces signalling via membrane-expressed BAFF and APRIL in myeloid cells., in PloS one, 8(4), 61350-61350.
Progesterone/RANKL is a major regulatory axis in the human breast.
Tanos Tamara, Sflomos George, Echeverria Pablo C, Ayyanan Ayyakkannu, Gutierrez Maria, Delaloye Jean-Francois, Raffoul Wassim, Fiche Maryse, Dougall William, Schneider Pascal, Yalcin-Ozuysal Ozden, Brisken Cathrin (2013), Progesterone/RANKL is a major regulatory axis in the human breast., in Science translational medicine, 5(182), 182-55.
Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.
Schmiedel Benjamin Joachim, Nuebling Tina, Steinbacher Julia, Malinovska Alexandra, Wende Constantin Maximilian, Azuma Miyuki, Schneider Pascal, Grosse-Hovest Ludger, Salih Helmut Rainer (2013), Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance., in Journal of immunology (Baltimore, Md. : 1950), 190(2), 821-31.
Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.
Schmiedel Benjamin Joachim, Nuebling Tina, Steinbacher Julia, Malinovska Alexandra, Wende Constantin Maximilian, Azuma Miyuki, Schneider Pascal, Grosse-Hovest Ludger, Salih Helmut Rainer (2013), Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance., in Journal of immunology (Baltimore, Md. : 1950), 190(2), 821-31.
Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions.
Pellegrini Maria, Willen Laure, Perroud Mai, Krushinskie Dennis, Strauch Kathy, Cuervo Hernan, Day Eric S, Schneider Pascal, Zheng Timothy S (2013), Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions., in The FEBS journal, 280(8), 1818-29.
The oncogene metadherin modulates the apoptotic pathway based on the tumor necrosis factor superfamily member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in breast cancer.
Zhang Ning, Wang Xiaolong, Huo Qiang, Li Xiaoyan, Wang Huiyun, Schneider Pascal, Hu Guohong, Yang Qifeng (2013), The oncogene metadherin modulates the apoptotic pathway based on the tumor necrosis factor superfamily member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in breast cancer., in The Journal of biological chemistry, 288(13), 9396-407.
Thy-1-mediated cell-cell contact induces astrocyte migration through the engagement of αVβ3 integrin and syndecan-4.
Kong Milene, Muñoz Nicolás, Valdivia Alejandra, Alvarez Alvaro, Herrera-Molina Rodrigo, Cárdenas Areli, Schneider Pascal, Burridge Keith, Quest Andrew F G, Leyton Lisette (2013), Thy-1-mediated cell-cell contact induces astrocyte migration through the engagement of αVβ3 integrin and syndecan-4., in Biochimica et biophysica acta, 1833(6), 1409-20.
Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-kappa B
Voutilainen M, Lindfors PH, Lefebvre S, Ahtiainen L, Fliniaux I, Rysti E, Murtoniemi M, Schneider P, Schmidt-Ullrich R, Mikkola ML (2012), Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-kappa B, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109(15), 5744-5749.
Identification of Ectodysplasin Target Genes Reveals the Involvement of Chemokines in Hair Development
Lefebvre S, Fliniaux I, Schneider P, Mikkola ML (2012), Identification of Ectodysplasin Target Genes Reveals the Involvement of Chemokines in Hair Development, in JOURNAL OF INVESTIGATIVE DERMATOLOGY, 132(4), 1094-1102.
The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade
Heinz LX, Rebsamen M, Rossi DC, Staehli F, Schroder K, Quadroni M, Gross O, Schneider P, Tschopp J (2012), The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade, in CELL DEATH AND DIFFERENTIATION, 19(4), 722-731.
The Design and Characterization of Receptor-selective APRIL Variants
Kimberley Fiona C, van der Sloot Almer M, Guadagnoli Marco, Cameron Katherine, Schneider Pascal, Marquart J Arnoud, Versloot Miranda, Serrano Luis, Medema Jan Paul (2012), The Design and Characterization of Receptor-selective APRIL Variants, in J Biol Chem, 287(44), 37434-37446.
Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.
Drexler Stefan K, Bonsignore Luca, Masin Mark, Tardivel Aubry, Jackstadt Rene, Hermeking Heiko, Schneider Pascal, Gross Olaf, Tschopp Jurg, Yazdi Amir S (2012), Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis., in Proceedings of the National Academy of Sciences of the United States of America, 109(45), 18384-18389.
Induction of the Alternative NF-kappa B Pathway by Lymphotoxin alpha beta (LT alpha beta) Relies on Internalization of LT beta Receptor
Ganeff C, Remouchamps C, Boutaffala L, Benezech C, Galopin G, Vandepaer S, Bouillenne F, Ormenese S, Chariot A, Schneider P, Caamano J, Piette J, Dejardin E (2011), Induction of the Alternative NF-kappa B Pathway by Lymphotoxin alpha beta (LT alpha beta) Relies on Internalization of LT beta Receptor, in MOLECULAR AND CELLULAR BIOLOGY, 31(21), 4319-4334.
Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies.
Kowalczyk Christine, Dunkel Nathalie, Willen Laure, Casal Margret L, Mauldin Elizabeth A, Gaide Olivier, Tardivel Aubry, Badic Giovanna, Etter Anne-Lise, Favre Manuel, Jefferson Douglas M, Headon Denis J, Demotz Stéphane, Schneider Pascal (2011), Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies., in The Journal of biological chemistry, 286(35), 30769-79.
Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells
Boeglin E, Smulski CR, Brun S, Milosevic S, Schneider P, Fournel S (2011), Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells, in PLOS ONE, 6(10), e25542-e25542.
A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells
Haselmayer P Vigolo M Nys J Schneider P Hess H, A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells, in Eur J Immunol .
TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus
Tran NL Schneider P Santiago-Raber ML, TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus, in Eur J Immunol .

Collaboration

Group / person Country
Types of collaboration
Dr Henry Hess, Merck-Serono, Darmstadt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- 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 Neil Kirby, EdimerPharma, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Dr Helmut Salih, Eberhard Karls University, Tuebingen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Olivier Gaide, UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr Kennet Huttner, EdimerPharma, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Dr Margaret Casal, University of Pennsylvania, Philadelphia United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr Gabriele Mues, Baylor College of Dentistry, Dallas United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr Fabienne Mackay, Garvan Insitute for Medical Research, Sydney Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
Dr Susan Kalled, BiogenIdec, Cambridge United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr Holm Schneider, University of Erlangen-Nürnberg, Erlangen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ZTZ opening symposium, University of Freiburg 2016 Talk given at a conference The B cell survival cytokines BAFF and APRIL: Mutants uncoupling receptor binding from biological effects reveal how BAFF signals 15.09.2016 Freiburg, Germany Schneider Pascal;
TMD Meeting, Helsinki 2016 Talk given at a conference Pharmacological manipulation of the EDA-EDAR pathway 13.06.2016 Porvoo, Finland Schneider Pascal;
Gordon Research Conference, Teeth and bones, Galveston 2016 Talk given at a conference Pharmacological manipulation of the EDA-EDAR pathway 14.02.2016 Galveston, United States of America Schneider Pascal;
15th International TNF Conference Ghent 2015 Talk given at a conference Mutants uncoupling receptor binding from biological effects reveal how the TNF family ligand BAFF/BLyS signals 20.05.2015 Ghent, Belgium Schneider Pascal;
TEDD Workshop Sion Disease cell-models, their use in industry Talk given at a conference Cell-based bioassays of the TNF superfamily 27.03.2014 Sion, Switzerland Schneider Pascal;
14th International TNF Conference Quebec 2013 Talk given at a conference Modifications of ectodermal appendages by manipulating the EDA-EDAR pair of TNF receptor and ligand 07.07.2013 Quebec, Canada Schneider Pascal;


Associated projects

Number Title Start Funding scheme
145002 Microscale thermophoresis for the Faculty of Bology and Medicine in Lausanne 01.12.2012 R'EQUIP
109443 Function of the TNF family ligands BAFF, APRIL and EDA 01.10.2005 Project funding (Div. I-III)
156961 TNF family ligands BAFF, APRIL and EDA 01.11.2014 Project funding (Div. I-III)
67927 Function of the TNF family ligands EDA, BAFF and APRIL 01.10.2002 Project funding (Div. I-III)
156961 TNF family ligands BAFF, APRIL and EDA 01.11.2014 Project funding (Div. I-III)
122553 Function of the TNF family ligands BAFF, APRIL and EDA 01.10.2008 Project funding (Div. I-III)

Abstract

BAFF/BLyS and APRIL are important for survival and development of peripheral B lymphocytes at various stages of differentiation. Ectodysplasin A (EDA) is essential for proper development of various ectodermal skin appendages, such as hair teeth and sweat glands. Despite their different functions, BAFF, APRIL and EDA are related members of the TNF family representing valuable therapeutic targets for the treatment of several diseases.In animal models of EDA-deficiency, a protein replacement approach was successful for long-term reversion of symptoms, provided that treatment was given at the time of normal development of EDA-dependent structures. Agonist anti-EDAR antibodies with potent in vivo activity were recently developed that open new perspectives for long-term treatment experiments in various animal models and possibly human. A recombinant form of EDA is in preclinical development, with phase I clinical trials planned to start within a year. With these reagents, there is a real hope to treat X-linked hypohidrotic ectodermal dysplasia (XL-HED) in human, a severe condition characterized, among other, by episodes of hyperthermia because of a lack of sweat glands, recurrent airways infections because mucous secreting glands function abnormally, and by severe teeth malformation. Using a pharmacological system in which we can control the dose, initiation time and termination time of EDA receptor (EDAR) signaling, we want to characterize precisely the dose and timing of administration that are required for development of a variety of EDA-dependent features in EDA-deficient mice. We also plan to determine whether tooth, hair and sweat gland development differ in their requirements for EDAR signals, and identify the molecular reason underlying loss of EDA-responsiveness after a certain time period. Another major endeavor is the identification of biomarkers of treatment activity. We will also address the physiological relevance of the observed interaction of EDA with proteoglycans.The biology of BAFF and APRIL is characterized by its complexity: it involves numerous forms of BAFF and APRIL, proteoglycans and three receptors, BCMA, TACI and BAFFR. BAFF is processed at a furin consensus cleavage site. Once processed, it can exist as soluble 3-mer or 60-mer. BAFF 60-mer, but not BAFF 3-mer can trigger signaling through TACI in primary B cells in vitro. We want to determine the physiologic function of large BAFF oligomers by analyzing the phenotype of knock-in mice in which BAFF cannot form 60-mers. We also will assess agonist and antagonist activity of BAFF-APRIL heteromers of defined stoechiometry in vitro and in vivo.Clinical trials with BAFF antagonists result in B cell depletion and decreased circulating antibody levels, as expected for blockade of a B cell survival factor. However, these trials also revealed unexpected effects, such as a transient increase of B cell numbers and exacerbation of symptoms in patients with multiple sclerosis. We will explore several hypotheses that could explain such an effect: removal of a TACI-mediated inhibition, depletion of IL10-producing regulatory B cells, and/or activation of myeloid cells through reverse BAFF-signaling.
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