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The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita¹

Sidonia Mihai^*, Mircea T. Chiriac^*, Kazue Takahashi, Joshua M. Thurman^,, V. Michael Holers^,, Detlef Zillikens^*, Marina Botto^¶ and Cassian Sitaru^2,*

^* Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Pediatrics, Laboratory of Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115; Department of Medicine and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80218; and ^¶ Rheumatology Section, Imperial College School of Medicine, London, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants Zi 439/6-2 and SI 1281/1-1 from the Deutsche Forschungsgemeinschaft (to C.S. and D.Z.) and National Institutes of Health Grants R01 AI-31105 (to V.M.H.) and K08 DK64790 (to J.M.T.).

² Address correspondence and reprint requests to Dr. Cassian Sitaru, Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, Lübeck, Germany. E-mail address: csitaru{at}fastmail.fm

³ Abbreviations used in this paper: EBA, epidermolysis bullosa acquisita; IF, immunofluorescence; Bf, complement factor B; MBL, mannan-binding lectin; MPO, myeloperoxidase; CR, complement receptor; WT, wild type.