title: Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and -independent manner.
abstract: In bullous pemphigoid (BP), the most prevalent autoimmune blistering disease, type XVII collagen (COL17) is targeted by circulating autoantibodies. BP is thought to be an autoantibody-mediated complement-fixing blistering disease, and a juxtamembranous noncollagenous 16A (NC16A) domain spanning Glu(490) to Arg(566) was proved to be the main pathogenic region on COL17, although precise pathogenic epitopes within NC16A have not been elucidated. In this study, we showed that injection of rabbit IgG Abs targeting Asp(522) to Gln(545) induced skin fragility associated with in vivo deposition of IgG and complement in neonatal COL17-humanized mice. Notably, immunoadsorption of rabbit anti-NC16A IgG Ab with this epitope (Asp(522) to Gln(545)) or the anti-NC16A IgG administered together with the peptides of this epitope as a decoy ameliorated skin fragility in the injected neonatal COL17-humanized mice compared with the anti-NC16A IgG alone even though all of the mice showed both IgG and complement deposition. These results led us to investigate an additional, complement-independent mechanism of skin fragility in the mice injected with anti-COL17 Abs. The rabbit anti-NC16A IgG depleted the expression of COL17 in cultured normal human keratinocytes, whereas immunoadsorption of the same IgG with this epitope significantly suppressed the depletion effect. Moreover, passive transfer of F(ab')(2) fragments of the human BP or rabbit IgG Abs against COL17 demonstrated skin fragility in neonatal COL17-humanized mice. In summary, this study reveals the importance of Abs directed against distinct epitopes on COL17, which induce skin fragility in complement-dependent as well as complement-independent ways.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan. natsuga@med.hokudai.ac.jp
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinkuma
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ujiie
authors.forename: Machiko
authors.initials: M
authors.lastname: Nishimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000008:administration & dosage* / Q000009:adverse effects; D001324:Autoantigens / Q000009:adverse effects / Q000276:immunology*; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology*; D000939:Epitopes / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024041:Non-Fibrillar Collagens / Q000009:adverse effects / Q000276:immunology*; D010391:Pemphigoid, Bullous / Q000276:immunology* / Q000473:pathology; D011817:Rabbits; D000097805:Collagen Type XVII
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D003165:Complement System Proteins; D000939:Epitopes; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII