{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:16:17Z","timestamp":1791994577890,"version":"4.4.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T00:00:00Z","timestamp":1489104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T00:00:00Z","timestamp":1489104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bullous pemphigoid (BP) is an autoimmune bullous disease caused by autoantibodies against BP180 in the epidermal basement membrane. Autoantibody-mediated complement activation is an important process in BP pathogenesis. CD46, a crucial complement regulatory protein in the complement activation, has been reported to be involved in several autoimmune diseases. In the present study, we investigated whether CD46 plays a role in BP development. We found that sCD46 expression was significantly increased in the serum and blister fluids of BP patients and correlated with the levels of anti-BP180 NC16A antibody and C3a. Otherwise, the level of mCD46 was decreased in lesions of BP patients, whereas the complement activation was enhanced. We also found that CD46 knockdown in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Importantly, exogenous CD46 blocked complement activation in both healthy skin sections and keratinocytes induced by exposure to pathogenic antibodies from BP patients. These data suggest that CD46 deficiency is an important factor in BP pathogenesis and that increasing CD46 levels might be an effective treatment for BP.<\/jats:p>","DOI":"10.1038\/s41598-017-00235-3","type":"journal-article","created":{"date-parts":[[2017,3,6]],"date-time":"2017-03-06T16:24:43Z","timestamp":1488817483000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Dysregulation of mCD46 and sCD46 contribute to the pathogenesis of bullous pemphigoid"],"prefix":"10.1038","volume":"7","author":[{"given":"Pei","family":"Qiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erle","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjiang","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,10]]},"reference":[{"key":"235_CR1","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/S0140-6736(99)03007-X","volume":"354","author":"HC Nousari","year":"1999","unstructured":"Nousari, H. C. & Anhalt, G. J. Pemphigus and bullous pemphigoid. Lancet \n                           354, 667\u2013672 (1999).","journal-title":"Lancet"},{"key":"235_CR2","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.yadr.2007.07.013","volume":"23","author":"G Di Zenzo","year":"2007","unstructured":"Di Zenzo, G., Marazza, G. & Borradori, L. Bullous Pemphigoid: Physiopathology, Clinical Features and Management. Advances in Dermatology \n                           23, 257\u2013288 (2007).","journal-title":"Advances in Dermatology"},{"key":"235_CR3","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1111\/j.1346-8138.2009.00792.x","volume":"37","author":"H Ujiie","year":"2010","unstructured":"Ujiie, H., Shibaki, A., Nishie, W. & Shimizu, H. What\u2019s new in bullous pemphigoid. J. Dermatol \n                           37, 194\u2013204 (2010).","journal-title":"J. Dermatol"},{"key":"235_CR4","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1172\/JCI117826","volume":"95","author":"Z Liu","year":"1995","unstructured":"Liu, Z. et al. The role of complement in experimental bullous pemphigoid. J. Clin. Invest. \n                           95, 1539\u20131544 (1995).","journal-title":"J. Clin. Invest."},{"key":"235_CR5","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.jaut.2008.08.009","volume":"31","author":"Z Liu","year":"2008","unstructured":"Liu, Z. et al. Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J. Autoimmun. \n                           31, 331\u2013338 (2008).","journal-title":"J. Autoimmun."},{"key":"235_CR6","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s12026-008-8028-y","volume":"41","author":"E Lessey","year":"2008","unstructured":"Lessey, E., Li, N., Diaz, L. & Liu, Z. Complement and cutaneous autoimmune blistering diseases. Immunologic Research \n                           41, 223\u2013232 (2008).","journal-title":"Immunologic Research"},{"key":"235_CR7","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.semnephrol.2013.08.001","volume":"33","author":"M Noris","year":"2013","unstructured":"Noris, M. & Remuzzi, G. Overview of complement activation and regulation. Semin. Nephrol. \n                           33, 479\u2013492 (2013).","journal-title":"Semin. Nephrol."},{"key":"235_CR8","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/S1567-5769(00)00043-6","volume":"1","author":"T Miwa","year":"2001","unstructured":"Miwa, T. & Song, W. C. Membrane complement regulatory proteins: insight from animal studies and relevance to human diseases. Int. Immunopharmacol. \n                           1, 445\u2013459 (2001).","journal-title":"Int. Immunopharmacol."},{"key":"235_CR9","doi-asserted-by":"publisher","first-page":"2808","DOI":"10.1016\/j.biocel.2013.09.016","volume":"45","author":"H Yamamoto","year":"2013","unstructured":"Yamamoto, H., Fara, A. F., Dasgupta, P. & Kemper, C. CD46: The \u2018multitasker\u2019 of complement proteins. Int. J. Biochem. Cell Biol. \n                           45, 2808\u20132820 (2013).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"235_CR10","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.it.2004.07.004","volume":"25","author":"RC Riley-Vargas","year":"2004","unstructured":"Riley-Vargas, R. C., Gill, D. B., Kemper, C., Liszewski, M. K. & Atkinson, J. P. CD46: Expanding beyond complement regulation. Trends in Immunology \n                           25, 496\u2013503 (2004).","journal-title":"Trends in Immunology"},{"key":"235_CR11","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/j.1365-2249.2011.04400.x","volume":"164","author":"J Cardone","year":"2011","unstructured":"Cardone, J., Le Friec, G. & Kemper, C. CD46 in innate and adaptive immunity: An update. Clinical and Experimental Immunology \n                           164, 301\u2013311 (2011).","journal-title":"Clinical and Experimental Immunology"},{"key":"235_CR12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s40246-015-0029-z","volume":"9","author":"MK Liszewski","year":"2015","unstructured":"Liszewski, M. K. & Atkinson, J. P. Complement regulator CD46: genetic variants and disease associations. Hum. Genomics \n                           9, 7 (2015).","journal-title":"Hum. Genomics"},{"key":"235_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cellimm.2012.06.008","volume":"277","author":"AP Alegretti","year":"2012","unstructured":"Alegretti, A. P., Schneider, L., Piccoli, A. K. & Xavier, R. M. The role of complement regulatory proteins in peripheral blood cells of patients with systemic lupus erythematosus: review. Cell Immunol \n                           277, 1\u20137 (2012).","journal-title":"Cell Immunol"},{"key":"235_CR14","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.cellimm.2010.07.013","volume":"265","author":"AP Alegretti","year":"2010","unstructured":"Alegretti, A. P. et al. Expression of CD55 and CD59 on peripheral blood cells from systemic lupus erythematosus (SLE) patients. Cell. Immunol. \n                           265, 127\u2013132 (2010).","journal-title":"Cell. Immunol."},{"key":"235_CR15","doi-asserted-by":"publisher","first-page":"725684","DOI":"10.1155\/2012\/725684","volume":"2012","author":"AP Alegretti","year":"2012","unstructured":"Alegretti, A. P. et al. Diminished expression of complement regulatory proteins on peripheral blood cells from systemic lupus erythematosus patients. Clin. Dev. Immunol. \n                           2012, 725684 (2012).","journal-title":"Clin. Dev. Immunol."},{"key":"235_CR16","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nri2620","volume":"9","author":"PF Zipfel","year":"2009","unstructured":"Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. \n                           9, 729\u2013740 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"235_CR17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.clim.2005.10.014","volume":"118","author":"DD Kim","year":"2006","unstructured":"Kim, D. D. & Song, W.-C. Membrane complement regulatory proteins. Clin. Immunol. \n                           118, 127\u2013136 (2006).","journal-title":"Clin. Immunol."},{"key":"235_CR18","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1590\/S0482-50042011000500009","volume":"51","author":"AK Piccoli","year":"2011","unstructured":"Piccoli, A. K., Alegretti, A. P., Schneider, L., Lora, P. S. & Xavier, R. M. Expression of complement regulatory proteins CD55, CD59, CD35, and CD46 in rheumatoid arthritis. Rev. Bras. Reumatol \n                           51, 497\u2013510 (2011).","journal-title":"Rev. Bras. Reumatol"},{"key":"235_CR19","doi-asserted-by":"publisher","first-page":"2892","DOI":"10.1172\/JCI17891","volume":"116","author":"KC Nelson","year":"2006","unstructured":"Nelson, K. C. et al. Role of different pathways of the complement cascade in experimental bullous pemphigoid. J. Clin. Invest. \n                           116, 2892\u20132900 (2006).","journal-title":"J. Clin. Invest."},{"key":"235_CR20","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/j.1399-0039.2004.00277.x","volume":"64","author":"S Russell","year":"2004","unstructured":"Russell, S. CD46: A complement regulator and pathogen receptor that mediates links between innate and acquired immune function. Tissue Antigens \n                           64, 111\u2013118 (2004).","journal-title":"Tissue Antigens"},{"key":"235_CR21","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.iac.2012.04.001","volume":"32","author":"H Ujiie","year":"2012","unstructured":"Ujiie, H., Nishie, W. & Shimizu, H. Pathogenesis of Bullous Pemphigoid. Immunology and Allergy Clinics of North America \n                           32, 207\u2013215 (2012).","journal-title":"Immunology and Allergy Clinics of North America"},{"key":"235_CR22","doi-asserted-by":"publisher","first-page":"4415","DOI":"10.4049\/jimmunol.1400095","volume":"193","author":"H Ujiie","year":"2014","unstructured":"Ujiie, H. et al. Bullous pemphigoid autoantibodies directly induce blister formation without complement activation. J. Immunol. \n                           193, 4415\u201328 (2014).","journal-title":"J. Immunol."},{"key":"235_CR23","doi-asserted-by":"publisher","first-page":"914","DOI":"10.2353\/ajpath.2010.090744","volume":"176","author":"G Wang","year":"2010","unstructured":"Wang, G. et al. Blockade of autoantibody-initiated tissue damage by using recombinant fab antibody fragments against pathogenic autoantigen. Am. J. Pathol. \n                           176, 914\u2013925 (2010).","journal-title":"Am. J. Pathol."},{"key":"235_CR24","first-page":"8411","volume":"16","author":"Y Zuo","year":"2016","unstructured":"Zuo, Y. et al. IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid. J Autoimmun \n                           16, 8411 (2016).","journal-title":"J Autoimmun"},{"key":"235_CR25","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.chom.2009.09.006","volume":"6","author":"PE Joubert","year":"2009","unstructured":"Joubert, P. E. et al. Autophagy Induction by the Pathogen Receptor CD46. Cell Host Microbe \n                           6, 354\u2013366 (2009).","journal-title":"Cell Host Microbe"},{"key":"235_CR26","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.imbio.2011.06.003","volume":"217","author":"S Ni Choileain","year":"2012","unstructured":"Ni Choileain, S. & Astier, A. L. CD46 processing: A means of expression. Immunobiology \n                           217, 169\u2013175 (2012).","journal-title":"Immunobiology"},{"key":"235_CR27","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1146\/annurev.immunol.22.012703.104549","volume":"22","author":"AP Manderson","year":"2004","unstructured":"Manderson, A. P., Botto, M. & Walport, M. J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. \n                           22, 431\u2013456 (2004).","journal-title":"Annu. Rev. Immunol."},{"key":"235_CR28","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1046\/j.1365-2249.1999.00917.x","volume":"116","author":"M Kawano","year":"1999","unstructured":"Kawano, M., Seya, T., Koni, I. & Mabuchi, H. Elevated serum levels of soluble membrane cofactor protein (CD46, MCP) in patients with systemic lupus erythematosus (SLE). Clin. Exp. Immunol. \n                           116, 542\u2013546 (1999).","journal-title":"Clin. Exp. Immunol."},{"key":"235_CR29","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1146\/annurev-med-072211-110606","volume":"64","author":"A Java","year":"2013","unstructured":"Java, A., Atkinson, J. & Salmon, J. Defective complement inhibitory function predisposes to renal disease. Annu. Rev. Med. \n                           64, 307\u201324 (2013).","journal-title":"Annu. Rev. Med."},{"key":"235_CR30","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1006\/mvre.2001.2342","volume":"62","author":"TG Lehmann","year":"2001","unstructured":"Lehmann, T. G. et al. Impact of inhibition of complement by sCR1 on hepatic microcirculation after warm ischemia. Microvasc. Res. \n                           62, 284\u201392 (2001).","journal-title":"Microvasc. Res."},{"key":"235_CR31","doi-asserted-by":"crossref","unstructured":"Schmidt, E. & Zillikens, D. The diagnosis and treatment of autoimmune blistering skin diseases. Dtsch. A\u0308rzteblatt Int. 108, 399\u2013405, I\u2013III (2011).","DOI":"10.3238\/arztebl.2011.0399"},{"key":"235_CR32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1093\/intimm\/dxs090","volume":"25","author":"M Kremlitzka","year":"2013","unstructured":"Kremlitzka, M. et al. Complement receptor type 1 (CR1, CD35) is a potent inhibitor of B-cell functions in rheumatoid arthritis patients. Int. Immunol. \n                           25, 25\u201333 (2013).","journal-title":"Int. Immunol."},{"key":"235_CR33","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1681\/ASN.2013010045","volume":"24","author":"Y Zhang","year":"2013","unstructured":"Zhang, Y. et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J. Am. Soc. Nephrol. \n                           24, 1820\u20139 (2013).","journal-title":"J. Am. Soc. Nephrol."},{"key":"235_CR34","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.molimm.2008.09.026","volume":"46","author":"R Khera","year":"2009","unstructured":"Khera, R. & Das, N. Complement Receptor 1: Disease associations and therapeutic implications. Molecular Immunology \n                           46, 761\u2013772 (2009).","journal-title":"Molecular Immunology"},{"key":"235_CR35","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/nbt1342","volume":"25","author":"D Ricklin","year":"2007","unstructured":"Ricklin, D. & Lambris, J. D. Complement-targeted therapeutics. Nat. Biotechnol. \n                           25, 1265\u20131275 (2007).","journal-title":"Nat. Biotechnol."},{"key":"235_CR36","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jdermsci.2013.05.010","volume":"72","author":"Y Wu","year":"2013","unstructured":"Wu, Y. et al. Anti-collagen XVII single-chain Fv antibody blocks the autoimmune reaction mediated by pathogenic autoantibodies in bullous pemphigoid. J. Dermatol. Sci. \n                           72, 25\u201331 (2013).","journal-title":"J. Dermatol. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00235-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00235-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00235-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:08:46Z","timestamp":1671764926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00235-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,10]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["235"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-00235-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,10]]},"assertion":[{"value":"25 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 February 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"145"}}