학술논문
Bullous pemphigoid induced by IgG targeting type XVII collagen non-NC16A/NC15A extracellular domains is driven by Fc gamma receptor- and complement-mediated effector mechanisms and is ameliorated by neonatal Fc receptor blockade.
Document Type
Academic Journal
Author
Pigors M; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Patzelt S; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Reichhelm N; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Dworschak J; Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany.; Khil'chenko S; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Emtenani S; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Bieber K; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Hofrichter M; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Kamaguchi M; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Goletz S; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Köhl G; Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.; Köhl J; Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Komorowski L; Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany.; Probst C; Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany.; Vanderheyden K; argenx, Ghent, Belgium.; Balbino B; argenx, Ghent, Belgium.; Ludwig RJ; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Department of Dermatology, Allergology and Venerology, University of Lübeck, Lübeck, Germany.; Verheesen P; argenx, Ghent, Belgium.; Schmidt E; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.; Department of Dermatology, Allergology and Venerology, University of Lübeck, Lübeck, Germany.
Source
Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE
Subject
Language
English
Abstract
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting type XVII collagen (Col17) with the noncollagenous 16A (NC16A) ectodomain representing the immunodominant site. The role of additional extracellular targets of Col17 outside NC16A has not been unequivocally demonstrated. In this study, we showed that Col17 ectodomain-reactive patient sera depleted in NC16A IgG induced dermal-epidermal separation in a cryosection model indicating the pathogenic potential of anti-Col17 non-NC16A extracellular IgG. Moreover, injection of IgG targeting the murine Col17 NC14-1 domains (downstream of NC15A, the murine homologue of human NC16A) into C57BL/6J mice resulted in erythematous skin lesions and erosions. Clinical findings were accompanied by IgG/C3 deposits along the basement membrane and subepidermal blistering with inflammatory infiltrates. Disease development was significantly reduced in either Fc-gamma receptor (FcγR)- or complement-5a receptor-1 (C5aR1)-deficient mice. Inhibition of the neonatal FcR (FcRn), an atypical FcγR regulating IgG homeostasis, with the murine Fc fragment IgG2c-ABDEG, a derivative of efgartigimod, reduced anti-NC14-1 IgG levels, resulting in ameliorated skin inflammation compared with isotype-treated controls. These data demonstrate that the pathogenic effects of IgG targeting the Col17 domain outside human NC16A/murine NC15A are partly attributable to antibody-mediated FcγR- and C5aR1 effector mechanisms while pharmacological inhibition of the FcRn represents a promising treatment for BP. The mouse model of BP will be instrumental in further investigating the role of Col17 non-NC16A/NC15A extracellular epitopes and validating new therapies for this disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
(© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
(© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)