title: Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model.
abstract: Bullous pemphigoid (BP) is an autoimmune blistering disease caused by IgG autoantibodies targeting the noncollagenous 16A (NC16A) domain of human collagen 17 (hCOL17), which triggers blister formation via complement activation. Previous in vitro analysis demonstrated that IgG1 autoantibodies showed much stronger pathogenic activity than IgG4 autoantibodies; however, the exact pathogenic role of IgG1 autoantibodies has not been fully demonstrated in vivo. We constructed a recombinant IgG1 mAb against hCOL17 NC16A from BP patients. In COL17-humanized mice, this mAb effectively reproduced a BP phenotype that included subepidermal blisters, deposition of IgG1, C1q and C3, neutrophil infiltration, and mast cell degranulation. Subsequently, alanine substitutions at various C1q binding sites were separately introduced to the Fc region of the IgG1 mAb. Among these mutated mAbs, the one that was mutated at the P331 residue completely failed to activate the complement in vitro and drastically lost pathogenic activity in COL17-humanized mice. These findings indicate that P331 is a key residue required for complement activation and that IgG1-dependent complement activation is essential for blister formation in BP. This study is, to our knowledge, the first direct evidence that IgG1 Abs to hCOL17 NC16A can induce blister formation in vivo, and it raises the possibility that IgG1 mAbs with Fc modification may be used to block pathogenic epitopes in autoimmune diseases.
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ujiie
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shibaki
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Reine
authors.initials: R
authors.lastname: Moriuchi
authors.forename: Hong-jiang
authors.initials: HJ
authors.lastname: Qiao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morioka
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinkuma
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.forename: Heather A
authors.initials: HA
authors.lastname: Long
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D001768:Blister / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D043170:Collagen Type XVIII / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015922:Complement C1q / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003176:Complement C3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007074:Immunoglobulin G / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010391:Pemphigoid, Bullous / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D043170:Collagen Type XVIII; D003176:Complement C3; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D015922:Complement C1q