SYNERGISTIC ACTIONS OF PEMPHIGUS VULGARIS IGG, FAS-LIGAND AND TUMOR NECROSIS FACTOR-A DURING INDUCTION OF BASAL CELL SHRINKAGE AND ACANTHOLYSIS.
This study by researchers at the University of California at Davis demonstrated that when MatTek’s EpiDerm-FT epidermal/dermal human skin tissue equivalents were treated with pemphigus vulgaris (PV) IgGs, it resulted in suprabasilar epidermal clefting and the cell detachment pattern characteristic of the acantholysis seen in the skin of pemphigus vulgaris patients. This study by researchers in the Dept. of Dermatology at the University of California at Davis tested a recently proposed “Basal Cell Shrinkage” hypothesis of pemphigus acantholysis through a quantitative analysis of individual and cooperative effects of pemphigus vulgaris (PV) IgG, Fas-ligand (Fas-L) and tumor necrosis factor-á (TNFá) on keratinocyte (KC) volume (i.e. cell size) and adhesive properties. Exposure of KC monolayers and MatTek EpiDermFT™ tissues to the physiologic concentrations of Fas-L, TNFá or IgGs from two PV patients resulted in various degrees of reversible changes, which were not observed in control cultures either exposed to normal IgG or left intact. Within 12—24 h of exposure, basal cells in experimental cultures lost their ability to form stress fibers, retracted cytoplasmic aprons and formed keratin aggregates, indicating that their cytoskeleton collapsed. The cell volume decreased significantly (p < 0.05) as the polygonal cell shape changed to a round one. The shrunk cells detached from their neighbors and the substrate, resulting in a reciprocal increase of both the areas of acantholysis and the number of detached KCs, respectively. Since in the skin of PV patients, KCs are targeted by autoantibodies concomitantly with being exposed to autocrine and paracrine pro-apoptotic and pro-inflammatory cytokines, we combined PV IgG with Fas-L and/or TNFá in the cell culture experiments. This amplified several fold an ability of PV IgG to cause basal cell shrinkage and detachment. The obtained results demonstrated for the first time that PV IgG works together with Fas-L and TNFá to induce acantholysis via basal cell shrinkage, which provides a novel mechanism explaining successful treatment of PV patients with TNFá inhibitors.
Acantholysis, Basal cell shrinkage, Cell detachment (acantholysis), Cell volume, Cytoplasmic aprons, EpiDerm-FT, EpiDermFT, Keratin aggregates, Pemphigus acantholysis, Pemphigus vulgaris, Stress fibers, Trypan blue dye (TBD)
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