title: B cells, dendritic cells, and macrophages are required to induce an autoreactive CD4 helper T cell response in experimental epidermolysis bullosa acquisita.
abstract: In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients' sera recognize the noncollagenous domain 1, including the von Willebrand factor A-like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany.
authors: Hiroaki
authors: H
authors: Iwata
authors: Katja
authors: K
authors: Bieber
authors: Benjamin
authors: B
authors: Tiburzy
authors: Navina
authors: N
authors: Chrobok
authors: Kathrin
authors: K
authors: Kalies
authors: Atsushi
authors: A
authors: Shimizu
authors: Sarah
authors: S
authors: Leineweber
authors: Akira
authors: A
authors: Ishiko
authors: Artem
authors: A
authors: Vorobyev
authors: Detlef
authors: D
authors: Zillikens
authors: Jörg
authors: J
authors: Köhl
authors: Jürgen
authors: J
authors: Westermann
authors: Karsten
authors: K
authors: Seeger
authors: Rudolf
authors: R
authors: Manz
authors: Ralf J
authors: RJ
authors: Ludwig
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002135:Calcium-Binding Proteins; D024143:Collagen Type VII / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016107:Epidermolysis Bullosa Acquisita / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D017434:Protein Structure, Tertiary; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D024143:Collagen Type VII; D016326:Extracellular Matrix Proteins; C496188:VWA2 protein, human; C480232:Vwa2 protein, mouse