title: The retinoid-related orphan receptor alpha is essential for the end-stage effector phase of experimental epidermolysis bullosa acquisita.
abstract: Genetic studies have added to the understanding of complex diseases. Here, we used a combined genetic approach for risk-loci identification in a prototypic, organ-specific, autoimmune disease, namely experimental epidermolysis bullosa acquisita (EBA), in which autoantibodies to type VII collagen (COL7) and neutrophil activation cause mucocutaneous blisters. Anti-COL7 IgG induced moderate blistering in most inbred mouse strains, while some showed severe disease or were completely protected. Using publicly available genotyping data, we identified haplotype blocks that control blistering and confirmed two haplotype blocks in outbred mice. To identify the blistering-associated genes, haplotype blocks encoding genes that are differentially expressed in EBA-affected skin were considered. This procedure identified nine genes, including retinoid-related orphan receptor alpha (RORα), known to be involved in neurological development and function. After anti-COL7 IgG injection, RORα+/- mice showed reduced blistering and homozygous mice were completely resistant to EBA induction. Furthermore, pharmacological RORα inhibition dose-dependently blocked reactive oxygen species (ROS) release from activated neutrophils but did not affect migration or phagocytosis. Thus, forward genomics combined with multiple validation steps identifies RORα to be essential to drive inflammation in experimental EBA.
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Hengameh
authors.initials: H
authors.lastname: Sadeghi
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Unni K
authors.initials: UK
authors.lastname: Samavedam
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Behnen
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Kasprick
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute of Anatomy, University of Lübeck, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Andreia
authors.initials: A
authors.lastname: de Castro Marques
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Recke
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Germany.
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256 B2A Biological Adaptation and Ageing, Paris, France.|CNRS, UMR 8256 B2A Biological Adaptation and Ageing, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Dermatology, University of Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D024143:Collagen Type VII / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D016107:Epidermolysis Bullosa Acquisita / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D007074:Immunoglobulin G / Q000276:immunology; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D024143:Collagen Type VII; D007074:Immunoglobulin G; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D017382:Reactive Oxygen Species; C539739:Rora protein, mouse; C561766:SR 3335; D013449:Sulfonamides; D013876:Thiophenes
keywords: RORα; animal models; autoimmunity; modulation; neutrophil; skin