{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:49:47Z","timestamp":1772164187859,"version":"3.50.1"},"reference-count":45,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2009,1]]},"abstract":"<jats:p>\n                    The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused primarily by autoantibodies against desmosomal cadherins. It was reported that apoptosis can be detected in pemphigus skin lesions and that apoptosis can be induced by PV-IgG in cultured keratinocytes. However, the role of apoptosis in PV pathogenesis is unclear at present. In this study, we provide evidence that apoptosis is not required for acantholysis in PV. In skin lesions from two PV patients, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positivity, but not cleaved caspase-3, was detected in single keratinocytes in some lesions but was completely absent in other lesions from the same patients. In cultures of human keratinocytes (HaCaT and normal human epidermal keratinocytes), PV-IgG from three different PV patients caused acantholysis, fragmented staining of Dsg 3 staining, and cytokeratin retraction in the absence of nuclear fragmentation, TUNEL positivity, and caspase-3 cleavage and hence in the absence of detectable apoptosis. To further rule out the contribution of apoptotic mechanisms, we used two different approaches that are effective to block apoptosis induced by various stimuli. Inhibition of caspases by z-VAD-fmk as well as overexpression of Fas-associated death domain-like interleukin-1\u03b2-converting enzyme (FLICE)-like inhibitory proteins FLIP\n                    <jats:sub>L<\/jats:sub>\n                    and FLIP\n                    <jats:sub>S<\/jats:sub>\n                    to inhibit receptor-mediated apoptosis did not block PV-IgG-induced effects, indicating that apoptosis was not required. Taken together, we conclude that apoptosis is not a prerequisite for skin blistering in PV but may occur secondary to acantholysis.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00161.2008","type":"journal-article","created":{"date-parts":[[2008,11,5]],"date-time":"2008-11-05T20:54:56Z","timestamp":1225918496000},"page":"C162-C172","source":"Crossref","is-referenced-by-count":47,"title":["Apoptosis is not required for acantholysis in pemphigus vulgaris"],"prefix":"10.1152","volume":"296","author":[{"given":"Enno","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Gutberlet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Siegmund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Berg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Wajant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Waschke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Amagai M\n                      , Hashimoto T, Shimizu N, Nishikawa T.\n                      Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.\n                      J Clin Invest\n                      94\n                      : 59\u201367, 1994.","DOI":"10.1172\/JCI117349"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Amagai M\n                      , Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa T.\n                      Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.\n                      J Clin Invest\n                      105\n                      : 625\u2013631, 2000.","DOI":"10.1172\/JCI8748"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Anhalt GJ\n                      , Labib RS, Voorhees JJ, Beals TF, Diaz LA.\n                      Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease.\n                      N Engl J Med\n                      306\n                      : 1189\u20131196, 1982.","DOI":"10.1056\/NEJM198205203062001"},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Aoyama Y\n                      , Owada MK, Kitajima Y.\n                      A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes.\n                      Eur J Immunol\n                      29\n                      : 2233\u20132240, 1999.","DOI":"10.1002\/(SICI)1521-4141(199907)29:07<2233::AID-IMMU2233>3.0.CO;2-4"},{"key":"R5","doi-asserted-by":"crossref","unstructured":"Arredondo J\n                      , Chernyavsky AI, Karaouni A, Grando SA.\n                      Novel mechanisms of target cell death and survival and of therapeutic action of IVIg in Pemphigus.\n                      Am J Pathol\n                      167\n                      : 1531\u20131544, 2005.","DOI":"10.1016\/S0002-9440(10)61239-4"},{"key":"R6","doi-asserted-by":"crossref","unstructured":"Baroni A\n                      , Buommino E, Paoletti I, Orlando M, Ruocco E, Ruocco V.\n                      Pemphigus serum and captopril induce heat shock protein 70 and inducible nitric oxide synthase overexpression, triggering apoptosis in human keratinocytes.\n                      Br J Dermatol\n                      150\n                      : 1070\u20131080, 2004.","DOI":"10.1111\/j.1365-2133.2004.05919.x"},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Berg D\n                      , Lehne M, Muller N, Siegmund D, Munkel S, Sebald W, Pfizenmaier K, Wajant H.\n                      Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L.\n                      Cell Death Differ\n                      14\n                      : 2021\u20132034, 2007.","DOI":"10.1038\/sj.cdd.4402213"},{"key":"R8","doi-asserted-by":"crossref","unstructured":"Berkowitz P\n                      , Hu P, Liu Z, Diaz LA, Enghild JJ, Chua MP, Rubenstein DS.\n                      Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization.\n                      J Biol Chem\n                      280\n                      : 23778\u201323784, 2005.","DOI":"10.1074\/jbc.M501365200"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Boukamp P\n                      , Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE.\n                      Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.\n                      J Cell Biol\n                      106\n                      : 761\u2013771, 1988.","DOI":"10.1083\/jcb.106.3.761"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Bretland AJ\n                      , Lawry J, Sharrard RM.\n                      A study of death by anoikis in cultured epithelial cells.\n                      Cell Prolif\n                      34\n                      : 199\u2013210, 2001.","DOI":"10.1046\/j.1365-2184.2001.00198.x"},{"key":"R11","doi-asserted-by":"crossref","unstructured":"Caldelari R\n                      , de Bruin A, Baumann D, Suter MM, Bierkamp C, Balmer V, Muller E.\n                      A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris.\n                      J Cell Biol\n                      153\n                      : 823\u2013834, 2001.","DOI":"10.1083\/jcb.153.4.823"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Calkins CC\n                      , Setzer SV, Jennings JM, Summers S, Tsunoda K, Amagai M, Kowalczyk AP.\n                      Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies.\n                      J Biol Chem\n                      281\n                      : 7623\u20137634, 2006.","DOI":"10.1074\/jbc.M512447200"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Chernyavsky AI\n                      , Arredondo J, Kitajima Y, Sato-Nagai M, Grando SA.\n                      Desmoglein vs. non-desmoglein signaling in pemphigus acantholysis: characterization of novel signaling pathways downstream of pemphigus vulgaris antigens.\n                      J Biol Chem\n                      282\n                      : 13804\u201313812, 2007.","DOI":"10.1074\/jbc.M611365200"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Chernyavsky AI\n                      , Arredondo J, Piser T, Karlsson E, Grando SA.\n                      Differential coupling of M1 muscarinic and alpha7 nicotinic receptors to inhibition of pemphigus acantholysis.\n                      J Biol Chem\n                      283\n                      : 3401\u20133408, 2008.","DOI":"10.1074\/jbc.M704956200"},{"key":"R15","doi-asserted-by":"crossref","unstructured":"Cirillo N\n                      , Lanza M, Rossiello L, Gombos F, Lanza A.\n                      Defining the involvement of proteinases in 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            39\n                      : 563\u2013575, 2006.","DOI":"10.1080\/08916930600971836"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Gniadecki R\n                      , Jemec GB, Thomsen BM, Hansen M.\n                      Relationship between keratinocyte adhesion and death: anoikis in acantholytic diseases.\n                      Arch Dermatol Res\n                      290\n                      : 528\u2013532, 1998.","DOI":"10.1007\/s004030050347"},{"key":"R21","doi-asserted-by":"crossref","unstructured":"Grando SA\n                      .\n                      Cholinergic control of epidermal cohesion.\n                      Exp Dermatol\n                      15\n                      : 265\u2013282, 2006.","DOI":"10.1111\/j.0906-6705.2006.00410.x"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Heupel WM\n                      , Zillikens D, Drenckhahn D, Waschke J.\n                      Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction.\n                      J Immunol\n                      181\n                      : 1825\u20131834, 2008.","DOI":"10.4049\/jimmunol.181.3.1825"},{"key":"R23","doi-asserted-by":"crossref","unstructured":"Huen AC\n                      , Park JK, Godsel LM, Chen X, Bannon LJ, Amargo EV, Hudson TY, Mongiu AK, Leigh IM, Kelsell DP, Gumbiner BM, Green KJ.\n                      Intermediate filament-membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength.\n                      J Cell Biol\n                      159\n                      : 1005\u20131017, 2002.","DOI":"10.1083\/jcb.200206098"},{"key":"R24","doi-asserted-by":"crossref","unstructured":"Ishii K\n                      , Harada R, Matsuo I, Shirakata Y, Hashimoto K, Amagai M.\n                      In vitro keratinocyte dissociation assay for evaluation of the pathogenicity of anti-desmoglein 3 IgG autoantibodies in pemphigus vulgaris.\n                      J Invest Dermatol\n                      124\n                      : 939\u2013946, 2005.","DOI":"10.1111\/j.0022-202X.2005.23714.x"},{"key":"R25","unstructured":"Majno G\n                      , Joris I.\n                      Apoptosis, oncosis, necrosis.An overview of cell death.\n                      Am J Pathol\n                      146\n                      : 3\u201315, 1995."},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Mascaro JM Jr\n                      , Espana A, Liu Z, Ding X, Swartz SJ, Fairley JA, and Diaz LA.\n                      Mechanisms of acantholysis in pemphigus vulgaris: role of IgG valence.\n                      Clin Immunol Immunopathol\n                      85\n                      : 90\u201396, 1997.","DOI":"10.1006\/clin.1997.4408"},{"key":"R27","doi-asserted-by":"crossref","unstructured":"Muller EJ\n                      , Williamson L, Kolly C, Suter MM.\n                      Outside-in signaling through integrins and cadherins: a central mechanism to control epidermal growth and differentiation?\n                      J Invest Dermatol\n                      128\n                      : 501\u2013516, 2008.","DOI":"10.1038\/sj.jid.5701248"},{"key":"R28","doi-asserted-by":"crossref","unstructured":"Osada K\n                      , Seishima M, Kitajima Y.\n                      Pemphigus IgG activates and translocates protein kinase C from the cytosol to the particulate\/cytoskeleton fractions in human keratinocytes.\n                      J Invest Dermatol\n                      108\n                      : 482\u2013487, 1997.","DOI":"10.1111\/1523-1747.ep12289726"},{"key":"R29","doi-asserted-by":"crossref","unstructured":"Pelacho B\n                      , Natal C, Espana A, Sanchez-Carpintero I, Iraburu MJ, and Lopez-Zabalza MJ.\n                      Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes.\n                      FEBS Lett\n                      566\n                      : 6\u201310, 2004.","DOI":"10.1016\/j.febslet.2004.03.107"},{"key":"R30","doi-asserted-by":"crossref","unstructured":"Peter ME\n                      , Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK, Owen LB, Pope RM, Tschopp J, Wajant H, Wallach D, Wiltrout RH, Zornig M, Lynch DH.\n                      The CD95 receptor: apoptosis revisited.\n                      Cell\n                      129\n                      : 447\u2013450, 2007.","DOI":"10.1016\/j.cell.2007.04.031"},{"key":"R31","doi-asserted-by":"crossref","unstructured":"Puviani M\n                      , Marconi A, Cozzani E, Pincelli C.\n                      Fas ligand in pemphigus sera induces keratinocyte apoptosis through the activation of caspase-8.\n                      J Invest Dermatol\n                      120\n                      : 164\u2013167, 2003.","DOI":"10.1046\/j.1523-1747.2003.12014.x"},{"key":"R32","doi-asserted-by":"crossref","unstructured":"Shimizu A\n                      , Ishiko A, Ota T, Tsunoda K, Amagai M, Nishikawa T.\n                      IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model.\n                      J Invest Dermatol\n                      122\n                      : 1145\u20131153, 2004.","DOI":"10.1111\/j.0022-202X.2004.22426.x"},{"key":"R33","doi-asserted-by":"crossref","unstructured":"Spindler V\n                      , Drenckhahn D, Zillikens D, Waschke J.\n                      Pemphigus IgG causes skin splitting in the presence of both desmoglein 1 and desmoglein 3.\n                      Am J Pathol\n                      171\n                      : 906\u2013916, 2007.","DOI":"10.2353\/ajpath.2007.070028"},{"key":"R34","doi-asserted-by":"crossref","unstructured":"Stanley JR\n                      , Amagai M.\n                      Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome.\n                      N Engl J Med\n                      355\n                      : 1800\u20131810, 2006.","DOI":"10.1056\/NEJMra061111"},{"key":"R35","doi-asserted-by":"crossref","unstructured":"Tiberio R\n                      , Marconi A, Fila C, Fumelli C, Pignatti M, Krajewski S, Giannetti A, Reed JC, Pincelli C.\n                      Keratinocytes enriched for stem cells are protected from anoikis via an integrin signaling pathway in a Bcl-2 dependent manner.\n                      FEBS Lett\n                      524\n                      : 139\u2013144, 2002.","DOI":"10.1016\/S0014-5793(02)03040-5"},{"key":"R36","doi-asserted-by":"crossref","unstructured":"Viard I\n                      , Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE.\n                      Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin.\n                      Science\n                      282\n                      : 490\u2013493, 1998.","DOI":"10.1126\/science.282.5388.490"},{"key":"R37","doi-asserted-by":"crossref","unstructured":"Wachter T\n                      , Sprick M, Hausmann D, Kerstan A, McPherson K, Stassi G, Brocker EB, Walczak H, Leverkus M.\n                      cFLIPL inhibits tumor necrosis factor-related apoptosis-inducing ligand-mediated NF-kappaB activation at the death-inducing signaling complex in human keratinocytes.\n                      J Biol Chem\n                      279\n                      : 52824\u201352834, 2004.","DOI":"10.1074\/jbc.M409554200"},{"key":"R38","doi-asserted-by":"crossref","unstructured":"Wajant H\n                      .\n                      Targeting the FLICE Inhibitory Protein (FLIP) in cancer therapy.\n                      Mol Interv\n                      3\n                      : 124\u2013127, 2003.","DOI":"10.1124\/mi.3.3.124"},{"key":"R39","doi-asserted-by":"crossref","unstructured":"Walsh M\n                      , Jayne D.\n                      Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future.\n                      Kidney Int\n                      72\n                      : 676\u2013682, 2007.","DOI":"10.1038\/sj.ki.5002395"},{"key":"R40","doi-asserted-by":"crossref","unstructured":"Wang X\n                      , Bregegere F, Frusic-Zlotkin M, Feinmesser M, Michel B, Milner Y.\n                      Possible apoptotic mechanism in epidermal cell acantholysis induced by pemphigus vulgaris autoimmunoglobulins.\n                      Apoptosis\n                      9\n                      : 131\u2013143, 2004.","DOI":"10.1023\/B:APPT.0000018795.05766.1f"},{"key":"R41","doi-asserted-by":"crossref","unstructured":"Wang X\n                      , Bregegere F, Soroka Y, Frusic-Zlotkin M, Milner Y.\n                      Replicative senescence enhances apoptosis induced by pemphigus autoimmune antibodies in human keratinocytes.\n                      FEBS Lett\n                      567\n                      : 281\u2013286, 2004.","DOI":"10.1016\/j.febslet.2004.04.083"},{"key":"R42","doi-asserted-by":"crossref","unstructured":"Waschke J\n                      .\n                      The desmosome and pemphigus.\n                      Histochem Cell Biol\n                      130\n                      : 21\u201354, 2008.","DOI":"10.1007\/s00418-008-0420-0"},{"key":"R43","doi-asserted-by":"crossref","unstructured":"Waschke J\n                      , Bruggeman P, Baumgartner W, Zillikens D, Drenckhahn D.\n                      Pemphigus foliaceus IgG causes dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction.\n                      J Clin Invest\n                      115\n                      : 3157\u20133165, 2005.","DOI":"10.1172\/JCI23475"},{"key":"R44","doi-asserted-by":"crossref","unstructured":"Waschke J\n                      , Spindler V, Bruggeman P, Zillikens D, Schmidt G, Drenckhahn D.\n                      Inhibition of Rho A activity causes pemphigus skin blistering.\n                      J Cell Biol\n                      175\n                      : 721\u2013727, 2006.","DOI":"10.1083\/jcb.200605125"},{"key":"R45","doi-asserted-by":"crossref","unstructured":"Wilgram GF\n                      , Caulfield JB, Lever WF.\n                      An electron microscopic study of acantholysis in pemphigus vulgaris.\n                      J Invest Dermatol\n                      36\n                      : 373\u2013382, 1961.","DOI":"10.1038\/jid.1961.58"}],"container-title":["American Journal of Physiology-Cell 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