The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita.
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.
Mihai
Sidonia
S
Department of Dermatology, University of Lübeck, Lübeck, Germany, and Department of Pediatrics, Laboratory of Developmental Immunology, Massachusetts General Hospital, Boston 02115, USA.
Chiriac
Mircea T
MT
Takahashi
Kazue
K
Thurman
Joshua M
JM
Holers
V Michael
VM
Zillikens
Detlef
D
Botto
Marina
M
Sitaru
Cassian
C
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
D001323:Autoantibodies; D024143:Collagen Type VII; D007074:Immunoglobulin G; D037601:Mannose-Binding Lectin; D015922:Complement C1q