{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:49:11Z","timestamp":1787003351113,"version":"build-2736575974"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:00:00Z","timestamp":1497484800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:00:00Z","timestamp":1497484800000},"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>\n                  <jats:p>\n                    Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1\u2009+\u2009aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-03697-7","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T06:36:17Z","timestamp":1496990177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus"],"prefix":"10.1038","volume":"7","author":[{"given":"Elias","family":"Walter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Vielmuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9862-218X","authenticated-orcid":false,"given":"Lukas","family":"Rotkopf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikl\u00f3s","family":"S\u00e1rdy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya N.","family":"Horv\u00e1th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Goebeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enno","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Eming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hertl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Spindler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Waschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,15]]},"reference":[{"key":"3697_CR1","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1056\/NEJMra061111","volume":"355","author":"JR Stanley","year":"2006","unstructured":"Stanley, J. R. & Amagai, M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N. Engl. J. Med. \n                           355, 1800\u201310, doi:10.1056\/NEJMra061111 (2006).","journal-title":"N. Engl. J. Med."},{"key":"3697_CR2","doi-asserted-by":"publisher","first-page":"a015297","DOI":"10.1101\/cshperspect.a015297","volume":"4","author":"JL Johnson","year":"2014","unstructured":"Johnson, J. L., Najor, N. A. & Green, K. J. Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease. Cold Spring Harb. Perspect. Med. \n                           4, a015297\u2013a015297, doi:10.1101\/cshperspect.a015297 (2014).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"3697_CR3","doi-asserted-by":"publisher","unstructured":"Kneisel, A. & Hertl, M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J. der Dtsch. Dermatologischen Gesellschaft\u2009=\u2009J. Ger. Soc. Dermatology JDDG \n                           9, 844\u201356; quiz 857 doi:10.1111\/j.1610-0387.2011.07793.x (2011).","DOI":"10.1111\/j.1610-0387.2011.07793.x"},{"key":"3697_CR4","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1111\/ajd.12154","volume":"55","author":"B Carew","year":"2014","unstructured":"Carew, B. & Wagner, G. Cutaneous pemphigus vulgaris with absence of desmoglein 1 autoantibodies. An example of the extended desmoglein compensation theory. Australas. J. Dermatol. \n                           55, 292\u20135, doi:10.1111\/ajd.2014.55.issue-4 (2014).","journal-title":"Australas. J. Dermatol."},{"key":"3697_CR5","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.jaad.2005.01.106","volume":"52","author":"K Yoshida","year":"2005","unstructured":"Yoshida, K. et al. Cutaneous type pemphigus vulgaris: a rare clinical phenotype of pemphigus. J. Am. Acad. Dermatol. \n                           52, 839\u201345, doi:10.1016\/j.jaad.2005.01.106 (2005).","journal-title":"J. Am. Acad. Dermatol."},{"key":"3697_CR6","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1046\/j.1523-1747.1999.00463.x","volume":"112","author":"Y Aoyama","year":"1999","unstructured":"Aoyama, Y. & Kitajima, Y. Pemphigus vulgaris-IgG causes a rapid depletion of desmoglein 3 (Dsg3) from the Triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous carcinoma cell line, DJM-1 cells. J. Invest. Dermatol. \n                           112, 67\u201371, doi:10.1046\/j.1523-1747.1999.00463.x (1999).","journal-title":"J. Invest. Dermatol."},{"key":"3697_CR7","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1038\/jid.2015.109","volume":"135","author":"E Sokol","year":"2015","unstructured":"Sokol, E. et al. Large-Scale Electron Microscopy Maps of Patient Skin and Mucosa Provide Insight into Pathogenesis of Blistering Diseases. J. Invest. Dermatol. \n                           135, 1763\u201370, doi:10.1038\/jid.2015.109 (2015).","journal-title":"J. Invest. Dermatol."},{"key":"3697_CR8","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/jid.1961.58","volume":"36","author":"GF Wilgram","year":"1961","unstructured":"Wilgram, G. F., Caulfield, J. B. & Lever, W. F. An electron microscopic study of acantholysis in pemphigus vulgaris. J. Invest. Dermatol. \n                           36, 373\u201382, doi:10.1038\/jid.1961.58 (1961).","journal-title":"J. Invest. Dermatol."},{"key":"3697_CR9","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1038\/jid.2014.21","volume":"134","author":"V Spindler","year":"2014","unstructured":"Spindler, V., Dehner, C., H\u00fcbner, S. & Waschke, J. 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Cell \n                           67, 869\u201377, doi:10.1016\/0092-8674(91)90360-B (1991).","journal-title":"Cell"},{"key":"3697_CR12","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1172\/JCI5252","volume":"103","author":"MG Mahoney","year":"1999","unstructured":"Mahoney, M. G. et al. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J. Clin. Invest. \n                           103, 461\u20138, doi:10.1172\/JCI5252 (1999).","journal-title":"J. Clin. Invest."},{"key":"3697_CR13","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.4049\/jimmunol.181.3.1825","volume":"181","author":"W-M Heupel","year":"2008","unstructured":"Heupel, W.-M., Zillikens, D., Drenckhahn, D. & Waschke, J. Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction. J. Immunol. (Baltimore, Md. 1950) \n                           181, 1825\u201334, doi:10.4049\/jimmunol.181.3.1825 (2008).","journal-title":"J. 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USA \n                           103, 12855\u201360, doi:10.1073\/pnas.0602973103 (2006).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"3697_CR22","doi-asserted-by":"publisher","first-page":"3068","DOI":"10.1038\/jid.2015.324","volume":"135","author":"F Vielmuth","year":"2015","unstructured":"Vielmuth, F., Waschke, J. & Spindler, V. Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus. J. Invest. Dermatol. \n                           135, 3068\u20133077, doi:10.1038\/jid.2015.324 (2015).","journal-title":"J. Invest. Dermatol."},{"key":"3697_CR23","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1172\/JCI60139","volume":"123","author":"V Spindler","year":"2013","unstructured":"Spindler, V. et al. Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering. J. Clin. Invest. \n                           123, 800\u201311, doi:10.1172\/JCI60139 (2013).","journal-title":"J. Clin. 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PLoS ONE \n                           7, e50696, doi:10.1371\/journal.pone.0050696 (2012).","journal-title":"PLoS ONE"},{"key":"3697_CR26","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1038\/jid.2014.140","volume":"134","author":"G van der Wier","year":"2014","unstructured":"van der Wier, G., Pas, H. H., Kramer, D., Diercks, G. F. H. & Jonkman, M. F. Smaller desmosomes are seen in the skin of pemphigus patients with anti-desmoglein 1 antibodies but not in patients with anti-desmoglein 3 antibodies. J. Invest. Dermatol. \n                           134, 2287\u201390, doi:10.1038\/jid.2014.140 (2014).","journal-title":"J. Invest. Dermatol."},{"key":"3697_CR27","doi-asserted-by":"publisher","first-page":"14925","DOI":"10.1074\/jbc.M113.527127","volume":"289","author":"V R\u00f6tzer","year":"2014","unstructured":"R\u00f6tzer, V., Breit, A., Waschke, J. & Spindler, V. Adducin is required for desmosomal cohesion in keratinocytes. J. Biol. 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