{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T08:33:50Z","timestamp":1789893230968,"version":"4.0.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2012,6,1]],"date-time":"2012-06-01T00:00:00Z","timestamp":1338508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 Glu490 to Arg566 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 Asp522 to Gln545 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 (Asp522 to Gln545) 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\u2032)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.<\/jats:p>","DOI":"10.4049\/jimmunol.1003402","type":"journal-article","created":{"date-parts":[[2012,4,21]],"date-time":"2012-04-21T04:57:45Z","timestamp":1334984265000},"page":"5792-5799","source":"Crossref","is-referenced-by-count":72,"title":["Antibodies to Pathogenic Epitopes on Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner"],"prefix":"10.1093","volume":"188","author":[{"given":"Ken","family":"Natsuga","sequence":"first","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Nishie","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Shinkuma","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Ujiie","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machiko","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Sawamura","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hirosaki University Graduate School of Medicine , Hirosaki 036-8562 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hokkaido University Graduate School of Medicine , Sapporo 0608638 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,6,1]]},"reference":[{"key":"2025032410121949400_r1","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1172\/JCI116368","article-title":"Human autoantibodies against the 230-kD bullous pemphigoid antigen (BPAG1) bind only to the intracellular domain of the hemidesmosome, whereas those against the 180-kD bullous pemphigoid antigen (BPAG2) bind along the plasma membrane of the hemidesmosome in normal human and swine skin","volume":"91","author":"Ishiko","year":"1993","journal-title":"J. Clin. Invest."},{"key":"2025032410121949400_r2","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1046\/j.1523-1747.2000.00136.x","article-title":"The extracellular domain of BPAG2 has a loop structure in the carboxy terminal flexible tail in vivo","volume":"115","author":"Nonaka","year":"2000","journal-title":"J. Invest. Dermatol."},{"key":"2025032410121949400_r3","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1074\/jbc.R400034200","article-title":"Collagenous transmembrane proteins: recent insights into biology and pathology","volume":"280","author":"Franzke","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2025032410121949400_r4","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.clindermatol.2011.01.010","article-title":"Ultrastructure and molecular pathogenesis of epidermolysis bullosa","volume":"29","author":"Shinkuma","year":"2011","journal-title":"Clin. Dermatol."},{"key":"2025032410121949400_r5","doi-asserted-by":"crossref","first-page":"8825","DOI":"10.1016\/S0021-9258(18)52948-3","article-title":"Cloning of type XVII collagen. Complementary and genomic DNA sequences of mouse 180-kilodalton bullous pemphigoid antigen (BPAG2) predict an interrupted collagenous domain, a transmembrane segment, and unusual features in the 5\u2032-end of the gene and the 3\u2032-untranslated region of the mRNA","volume":"268","author":"Li","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2025032410121949400_r6","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1046\/j.1523-1747.1998.00363.x","article-title":"The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1","volume":"111","author":"Shimizu","year":"1998","journal-title":"J. Invest. Dermatol."},{"key":"2025032410121949400_r7","first-page":"333","article-title":"Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta","volume":"18","author":"Nakamura","year":"2006","journal-title":"Int. J. Mol. Med."},{"key":"2025032410121949400_r8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/ng0995-83","article-title":"Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa","volume":"11","author":"McGrath","year":"1995","journal-title":"Nat. Genet."},{"key":"2025032410121949400_r9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2353\/ajpath.2009.080573","article-title":"Type XVII collagen is a key player in tooth enamel formation","volume":"174","author":"Asaka","year":"2009","journal-title":"Am. J. Pathol."},{"key":"2025032410121949400_r10","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1582-4934.2007.00033.x","article-title":"Immunopathology and molecular diagnosis of autoimmune bullous diseases","volume":"11","author":"Mihai","year":"2007","journal-title":"J. Cell. Mol. Med."},{"key":"2025032410121949400_r11","doi-asserted-by":"crossref","first-page":"5742","DOI":"10.4049\/jimmunol.151.10.5742","article-title":"Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain","volume":"151","author":"Giudice","year":"1993","journal-title":"J. Immunol."},{"key":"2025032410121949400_r12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/0738-081X(87)90056-3","article-title":"Animal models for bullous pemphigoid","volume":"5","author":"Anhalt","year":"1987","journal-title":"Clin. 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Dermatol."},{"key":"2025032410121949400_r18","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1046\/j.1523-1747.2002.19529.x","article-title":"Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain","volume":"119","author":"Hofmann","year":"2002","journal-title":"J. Invest. Dermatol."},{"key":"2025032410121949400_r19","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.0022-202X.2003.22126.x","article-title":"Characterization of the anti-BP180 autoantibody reactivity profile and epitope mapping in bullous pemphigoid patients","volume":"122","author":"Di Zenzo","year":"2004","journal-title":"J. Invest. Dermatol."},{"key":"2025032410121949400_r20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.1523-1747.1998.00107.x","article-title":"Epitope spreading: lessons from autoimmune skin diseases","volume":"110","author":"Chan","year":"1998","journal-title":"J. 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Immunol."},{"key":"2025032410121949400_r45","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/1523-1747.ep12337492","article-title":"Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies","volume":"109","author":"Zillikens","year":"1997","journal-title":"J. Invest. Dermatol."},{"key":"2025032410121949400_r46","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/j.0022-202X.2005.23853.x","article-title":"Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphigoid","volume":"125","author":"Fairley","year":"2005","journal-title":"J. Invest. 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