title: Genetic identification and functional validation of FcγRIV as key molecule in autoantibody-induced tissue injury.
abstract: Autoantibody-mediated diseases are clinically heterogeneous and often fail conventional therapeutic strategies. Gene expression profiling has helped to identify new molecular pathways in these diseases, although their potential as treatment targets largely remains to be functionally validated. Based on weighted gene co-expression network analysis, we determined the transcriptional network in experimental epidermolysis bullosa acquisita (EBA), a paradigm of an antibody-mediated organ-specific autoimmune disease characterized by autoantibodies directed against type VII collagen. We identified 33 distinct and differentially expressed modules, including Fcγ receptor (FcγR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcγRIV expression on neutrophils crucially contributes to autoantibody-induced tissue injury in the transfer model of EBA. Mice lacking the common γ-chain of activating FcγRs, deficient in FcγRIV or treated with FcγRIV function blocking antibody, but not mice deficient in FcγRI, FcγRIIB, FcγRIII or both FcγRI and FcγRIII, were effectively protected from EBA. Skin disease was restored in γ-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from γ-chain-deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcγRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies.
authors.affiliation: Department of Dermatology, University of Lübeck, Germany. Michael.Kasperkiewicz@uk-sh.de
authors.forename: Michael
authors.initials: M
authors.lastname: Kasperkiewicz
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Sabina
authors.initials: S
authors.lastname: Wende
authors.forename: Misa
authors.initials: M
authors.lastname: Hirose
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwata
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.forename: Unni
authors.initials: U
authors.lastname: Samavedam
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.forename: Ellen
authors.initials: E
authors.lastname: Rentz
authors.forename: Lars
authors.initials: L
authors.lastname: Hellberg
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
authors.forename: Jürgen
authors.initials: J
authors.lastname: Westermann
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D024143:Collagen Type VII / Q000276:immunology; D004195:Disease Models, Animal; D016107:Epidermolysis Bullosa Acquisita / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D009928:Organ Specificity; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D001323:Autoantibodies; D024143:Collagen Type VII; C522404:Fcgr4 protein, mouse; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG