IgG antibodies against immunodominant C-terminal epitopes of BP230 do not induce skin blistering in mice.
Bullous pemphigoid, the most common autoimmune blistering disease in Western Europe and the USA is characterized by the presence of circulating and tissue-bound autoantibodies against the hemidesmosomal proteins BP230 and BP180/collagen XVII. After binding to their target antigens at the basement membrane of the dermal-epidermal junction these autoantibodies are thought to trigger an inflammatory cascade comprising complement- and granulocyte-dependent reactions that result in tissue damage. Whereas the role of anti-BP180 antibodies has been extensively characterized, few and conflicting data is available on the contribution of anti-BP230 antibodies to bullous pemphigoid pathogenesis. Therefore, we addressed in the present study the role of autoantibodies to BP230 in experimental bullous pemphigoid. Rabbit polyclonal antibodies generated against epitopes of the C-terminal fragment of murine BP230 bound to the basement membrane and activated the complement system ex vivo. Affinity-purified antibodies were subsequently subcutaneously transferred into neonatal and adult BALB/c mice. In vivo, we observed a dose-dependent binding of transferred antibodies in the murine skin; however, there was no complement activation and these mice showed no clinical or histological signs of inflammatory disease, in contrast to mice receiving anti-BP180 antibodies. We further conducted ex vivo experiments and demonstrated that rabbit IgG anti-BP230-specific antibodies, in contrast to antibodies from bullous pemphigoid patients or rabbit IgG anti-BP180 antibodies used as positive controls, did not activate human granulocytes to induce dermal-epidermal separation in skin cryosections. Our present findings demonstrate that antibodies against BP230 are non-pathogenic in experimental models of bullous pemphigoid and suggest that proper activation of the complement and granulocytes represent prerequisites for conferring bullous pemphigoid autoantibodies their tissue destructive potential.
Faculty of Medicine, Iuliu-Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Dermatology, University of Freiburg, Freiburg, Germany.
Vasile
V
Feldrihan
Department of Dermatology, University of Freiburg, Freiburg, Germany; Department of Biology, Babes-Bolyai University, Cluj-Napoca, Romania.
Emilia
E
Licarete
Department of Dermatology, University of Freiburg, Freiburg, Germany.
Florina
F
Florea
Faculty of Medicine, Iuliu-Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
Victor
V
Cristea
Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania; Institute of Biology, Romanian Academy, Bucharest, Romania.
Octavian
O
Popescu
Department of Dermatology, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: cassian@mail.sitaru.eu.
Cassian
C
Sitaru
Department of Biology, Babes-Bolyai University, Cluj-Napoca, Romania; Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania; Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: mtchiriac@yahoo.com.
Mircea Teodor
MT
Chiriac
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001324:Autoantigens / Q000276:immunology; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020405:Dermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000071821:Dystonin; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens / Q000276:immunology; D010391:Pemphigoid, Bullous / Q000276:immunology*; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D000097805:Collagen Type XVII
D001324:Autoantigens; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D011993:Recombinant Fusion Proteins; D000097805:Collagen Type XVII; C000592701:BP230 protein, mouse; C486268:DST protein, human