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. Current pemphigus research is elucidating new mechanisms of keratinocyte detachment in pemphigus vulgaris (PV) that lead to blistering. Identification of the key pathophysiologic elements will facilitate pharmacologic development of agents to prevent this breakdown in epidermal integrity. The classic studies demonstrating that PVIgG can induce suprabasal acantholysis -a histopathologic hallmark of PV -even in the skin of neonatal mice lacking either desmoglein (Dsg) 3 (1), plasminogen activator (2), or complement activity (3) narrowed the search for the pathophysiologically relevant targets. The results of the study by Pretel et al. (4) published in this issue of Experimental Dermatology underscore the most important pathophysiologic mechanisms in skin of PV patients. In a series of elegant experiments, these authors convincingly demonstrate that acantholysis in PV develops secondary to the PVIgGinduced EGF receptor (EGFR) ⁄ Src signalling that activates an apoptotic cascade through the serine ⁄ threonine protein kinase, mTOR. Furthermore, the suprabasal split occurs due to differences between basal and suprabasal cells in their responses to PVIgG, as was predicted by the Basal Cell Shrinkage hypothesis (5). The data presented by Pretel et al. (4), taken together with a bulk of in vitro and in vivo results reported in the literature, establish a novel paradigm where PVIgG signalling links the suprabasal acantholytic and apoptotic pathways to basal cell shrinkage. In marked

Desmosome assembly, homeostasis, and desmosomal disease

“…Additional desmosomal autoantigens include Dscs, such Dsc3, 138,139 as well as Pg, 140 Dsp, 141 and Pkp3. 142 Insights into pathomechanisms underlying the generation of acantholysis in PV after autoantibodies bind to desmosomal and nondesmosomal antigens on the keratinocyte surface have lead to two conflicting, yet complementary hypotheses. The first hypothesis proposes that anti-Dsg3 antibody interferes with intercellular adhesive function(s) of Dsg3 either by steric hindrance or by outside-in signaling, leading directly to desmosomal dissociation.…”

Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

“…This is explained by Dsg1 expressed in high amounts in the epidermis, which compensates for the loss of Dsg3 function when only this isoform is targeted (5). Although the desmoglein compensation theory is discussed controversially (6,7), it can be considered likely that desmosomal cadherins compensate the adhesive function of each other (8). Furthermore, it is well established that autoantibody-induced signaling is necessary for pronounced blistering (9,10).…”

New capabilities of the complex pathogenetic therapy of patients with pemphigus vulgaris

“…населения в год), ВП отличается тяжелым течением и угрозой для жизни больного в отсутствие адекват-ной иммуносупрессивной терапии [2][3][4][5][6].…”

“…В патогенезе ВП ведущую роль играют аутоим-мунные механизмы, в результате которых запуска-ются процессы распознавания антигенпрезентиру-ющими клетками собственных молекул -десмогле-инов, входящих в состав десмосом, происходит от-мена толерантности Т-и В-клеток к собственным аутоантигенам, синтезируются аутоантитела класса IgG4, развивается акантолиз и образуются полости в эпидермисе, в которые проникает межтканевая жидкость [1,3,4,[6][7][8][9][10][11].…”