title: IgG4 autoantibodies induce dermal-epidermal separation.
abstract: Bullous pemphigoid (BP) is a sub-epidermal autoimmune blistering disease associated with autoantibodies to the dermal-epidermal junction (DEJ). Patients' autoantibodies induce dermal-epidermal separation when co-incubated with cryosections of human skin and leucocytes from healthy volunteers. IgG autoantibodies trigger complement and/or leucocyte activation resulting in specific pathology in several autoimmune conditions. In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage. The capacity of IgG4 autoantibodies to mediate tissue damage has not yet been demonstrated. In this study, we isolated IgG1 and IgG4 autoantibodies from bullous pemhigoid patients'serum and analysed their blister-inducing potential in our cryosection assay. As expected, complement-fixing IgG1 autoantibodies induced sub-epidermal splits in this experimental model. Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation. The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1. Our results demonstrate that IgG4 autoantibodies are able to activate leucocytes and point to a hitherto less recognized function of IgG4. Moreover, for the first time, we clearly demonstrate that BP IgG4 autoantibodies have the capacity to induce leucocyte-dependent tissue damage.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Sidonia
authors.initials: S
authors.lastname: Mihai
authors.forename: Mircea T
authors.initials: MT
authors.lastname: Chiriac
authors.forename: Josep E
authors.initials: JE
authors.lastname: Herrero-González
authors.forename: Margaret
authors.initials: M
authors.lastname: Goodall
authors.forename: Roy
authors.initials: R
authors.lastname: Jefferis
authors.forename: Caroline O S
authors.initials: CO
authors.lastname: Savage
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology*; D001485:Basement Membrane / Q000187:drug effects / Q000276:immunology; D001768:Blister / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion; D002846:Chromatography, Affinity; D003165:Complement System Proteins / Q000276:immunology; D016616:Cryoultramicrotomy; D020405:Dermis / Q000276:immunology* / Q000473:pathology*; D004817:Epidermis / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification / Q000276:immunology* / Q000302:isolation & purification; D007962:Leukocytes / Q000473:pathology; D010391:Pemphigoid, Bullous / Q000097:blood / Q000276:immunology / Q000473:pathology*
chemical_list: D019138:Antibodies, Blocking; D001323:Autoantibodies; D007074:Immunoglobulin G; D003165:Complement System Proteins