title: The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.
abstract: BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Franziska S
authors.initials: FS
authors.lastname: Hoffmann
authors.affiliation: Neuroproteomics, Technical University Munich and Hospital Rechts der Isar, Munich D-81675, Germany; German Center for Neurodegenerative Diseases, Bonn D-53175, Germany; Institute for Advanced Study, Technical University, Munich D-85748, Germany;
authors.forename: Peer-Hendrik
authors.initials: PH
authors.lastname: Kuhn
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Laurent
authors.affiliation: Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg D-85764, Germany;
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried D-82152, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Berer
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Simone A
authors.initials: SA
authors.lastname: Wendlinger
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Krumbholz
authors.affiliation: Division of Clinical Neuroscience, Karolinska University Hospital, Stockholm 14186, Sweden;
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.affiliation: Division of Clinical Neuroscience, Karolinska University Hospital, Stockholm 14186, Sweden;
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Department of Medicine III, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Department of Neurology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin D-10117, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin D-10117, Germany;
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel
authors.affiliation: Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL 32224; and.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried D-82152, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Wekerle
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: Neuroproteomics, Technical University Munich and Hospital Rechts der Isar, Munich D-81675, Germany; German Center for Neurodegenerative Diseases, Bonn D-53175, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany; edgar.meinl@med.uni-muenchen.de.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007074:Immunoglobulin G; D008565:Membrane Proteins; C108467:TNFRSF13B protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; C486361:Tnfrsf13b protein, mouse; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse