Forskning ved Københavns Universitet - Københavns Universitet


Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • S.A. Grando
  • J.C. Bystryn
  • A.I. Chernyavsky
  • M. Frusic-Zlotkin
  • R. Gniadecki
  • R. Lotti
  • Y. Milner
  • M.R. Pittelkow
  • C. Pincelli
Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a 'tombstone' appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. (1) Binding of autoantibodies to PV antigens. (2) Activation of EGF receptor, Src, mTOR, p38 MAPK and other signalling elements downstream of ligated antigens, elevation of intracellular calcium and launching of the cell death cascades. (3) Basal cell shrinkage due to: (i) collapse and retraction of the tonofilaments cleaved by executioner caspases; and (ii) dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules. (4) Massive cleavage of cellular proteins by activated cell death enzymes leading to cell collapse, and tearing off desmosomes from the cell membrane stimulating secondary autoantibody production. (5) Rounding up and death of acantholytic cells. Thus, the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same cell death enzymes. Appreciation of the unifying concept of apoptolysis have several important implications: (i) linking together a number of seemingly unrelated events surrounding acantholysis; (ii) opening new avenues of investigation into the pathomechanism of pemphigus; and (iii) creating new approaches to the treatment of pemphigus based on blocking the signalling pathways and enzymatic processes that lead to blistering
Udgivelsesdato: 2009/9
TidsskriftExperimental Dermatology
Udgave nummer9
Sider (fra-til)764-770
Antal sider6
StatusUdgivet - 2009

Bibliografisk note

Times Cited: 1ArticleEnglishGrando, S. AUniv Calif Irvine, Inst Immunol, 134 Sprague Hall, Irvine, CA 92697 USACited References Count: 61482YCWILEY-BLACKWELL PUBLISHING, INCCOMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USAMALDEN

ID: 20656081