title: The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
abstract: Epidermolysis bullosa acquisita is a subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against type VII collagen, a major constituent of the dermal-epidermal junction. The passive transfer of Abs against type VII collagen into mice induces a subepidermal blistering disease dependent upon activation of terminal complement components. To further dissect the role of the different complement activation pathways in this model, we injected C1q-deficient, mannan-binding lectin-deficient, and factor B-deficient mice with rabbit Abs against murine type VII collagen. The development and evolution of blistering had a similar pattern in mannan-binding lectin-deficient and control mice and was initially only marginally less extensive in C1q-deficient mice compared with controls. Importantly, factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice. A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice. Our study provides the first direct evidence for the involvement of the alternative pathway in an autoantibody-induced blistering disease and should facilitate the development of new therapeutic strategies for epidermolysis bullosa acquisita and related autoimmune diseases.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany, and Department of Pediatrics, Laboratory of Developmental Immunology, Massachusetts General Hospital, Boston 02115, USA.
authors.forename: Sidonia
authors.initials: S
authors.lastname: Mihai
authors.forename: Mircea T
authors.initials: MT
authors.lastname: Chiriac
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage; D001768:Blister / Q000235:genetics / Q000276:immunology*; D024143:Collagen Type VII / Q000276:immunology; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D016107:Epidermolysis Bullosa Acquisita / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000008:administration & dosage; D037601:Mannose-Binding Lectin / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001323:Autoantibodies; D024143:Collagen Type VII; D007074:Immunoglobulin G; D037601:Mannose-Binding Lectin; D015922:Complement C1q