title: Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis.
abstract: 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.
authors: Institute for Immunology and Department of Dermatology, University of California, Irvine, CA 92697, USA. sgrando@uci.edu
authors: Sergei A
authors: SA
authors: Grando
authors: Jean-Claude
authors: JC
authors: Bystryn
authors: Alexander I
authors: AI
authors: Chernyavsky
authors: Marina
authors: M
authors: Frusić-Zlotkin
authors: Robert
authors: R
authors: Gniadecki
authors: Roberta
authors: R
authors: Lotti
authors: Yoram
authors: Y
authors: Milner
authors: Mark R
authors: MR
authors: Pittelkow
authors: Carlo
authors: C
authors: Pincelli
mesh_terms: D000051:Acantholysis; D000818:Animals; D017209:Apoptosis; D001768:Blister / Q000209:etiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D010392:Pemphigus / Q000378:metabolism / Q000503:physiopathology*