title: Death receptor 6 contributes to autoimmunity in lupus-prone mice.
abstract: Expansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE). Here we show expression of an orphan immune regulator, death receptor 6 (DR6/TNFRSF21), on a population of Tfh cells that are highly expanded in lupus-like disease progression in mice. Genome-wide screening reveals an interaction between syndecan-1 and DR6 resulting in immunosuppressive functions. Importantly, syndecan-1 is expressed specifically on autoreactive germinal centre (GC) B cells that are critical for maintenance of Tfh cells. Syndecan-1 expression level on GC B cells is associated with Tfh cell expansion and disease progression in lupus-prone mouse strains. In addition, Tfh cell suppression by DR6-specific monoclonal antibody delays disease progression in lupus-prone mice. These findings suggest that the DR6/syndecan-1 axis regulates aberrant GC reactions and could be a therapeutic target for autoimmune diseases such as SLE.
authors.affiliation: Division of Infection and Immunity, Hokkaido University Research Center for Zoonosis Control, North-20, West-10, Kita-ku, Sapporo 001-0020, Japan.|Division of Molecular Immunology, Hokkaido University Institute for Genetic Medicine, North-15, West-7, Kita-ku, Sapporo 060-0815, Japan.|Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, North-20, West-10, Kita-ku, Sapporo 001-0020, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujikura
authors.affiliation: Division of Molecular Immunology, Hokkaido University Institute for Genetic Medicine, North-15, West-7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikesue
authors.affiliation: Division of Molecular Immunology, Hokkaido University Institute for Genetic Medicine, North-15, West-7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Endo
authors.affiliation: Division of Infection and Immunity, Hokkaido University Research Center for Zoonosis Control, North-20, West-10, Kita-ku, Sapporo 001-0020, Japan.|Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, North-20, West-10, Kita-ku, Sapporo 001-0020, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Infection and Immunity, Hokkaido University Research Center for Zoonosis Control, North-20, West-10, Kita-ku, Sapporo 001-0020, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Higashi
authors.affiliation: Division of Molecular Immunology, Hokkaido University Institute for Genetic Medicine, North-15, West-7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D016678:Genome; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D053668:Syndecan-1 / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018124:Receptors, Tumor Necrosis Factor; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; C485251:Tnfrsf21 protein, mouse