title: Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibility for autoimmune blistering diseases.
abstract: Low-affinity Fcγ receptors (FcγR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcγR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcγR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcγR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcγR. In a two-stage study, we analyzed whether the FcγR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcγR genes affect FcγR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcγR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcγR genotype association patterns, pointing towards different disease etiologies.
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: Andreas.Recke@uksh.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Recke
authors.affiliation: Department of Experimental Hematology, Sanquin Research Institute, Amsterdam, The Netherlands.
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Freitag
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Vonthein
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schellenberger
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Ozan
authors.initials: O
authors.lastname: Haase
authors.affiliation: Department of Transfusion Medicine, University of Lübeck, Lübeck, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Görg
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Flachsbart
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Epidemiology, Christian-Albrechts-University, Kiel, Germany; popgen Biobank, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Department of Dermatology, Allergology and Venereology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Gläser
authors.affiliation: Department of Dermatology, Allergology and Venereology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Benoit
authors.affiliation: Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sárdy
authors.affiliation: Department of Dermatology and Allergology, Philipp University of Marburg, Marburg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Eming
authors.affiliation: Department of Dermatology and Allergology, Philipp University of Marburg, Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hertl
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany; Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: Saleh.Ibrahim@uksh.de.
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D001768:Blister / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006098:Granulocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*
chemical_list: C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017382:Reactive Oxygen Species; D017452:Receptors, IgG
keywords: Autoantibodies; Autoimmune blistering dermatoses; Fcγ receptors; Functional genetics; Joint copy number and allelic variation; Neutrophils; Reactive oxygen species