The Interaction of Pemphigus Autoimmunoglobulins with Epidermal Cells: Activation of the Fas Apoptotic Pathway and the Use of Caspase Activity for Pathogenicity Tests of Pemphigus Patients

• Published in: Annals of the New York Academy of Sciences 2005-06, Vol.1050 (1), p.371-379
• Main Authors: FRUŠIĆ-ZLOTKIN, MARINA, PERGAMENTZ, ROCHEL, MICHEL, BENO, DAVID, MICHAEL, MIMOUNI, DANIEL, BRÉGÉGÈRE, FRANÇOIS, MILNER, YORAM
• Format: Article
• Language: English
• Subjects: acantholysis; Acantholysis - immunology; apoptosis; Apoptosis - immunology; Autoantibodies - immunology; Autoimmunity; Blotting, Western; Caspase Inhibitors; Caspases - metabolism; Cells, Cultured; Enzyme Activation; Epidermis - immunology; Fluorescent Antibody Technique, Indirect; Humans; Immunoglobulin G; Keratinocytes - enzymology; Keratinocytes - immunology; Keratinocytes - metabolism; Kinetics; Organ Culture Techniques; Pemphigus - immunology; pemphigus IgG; Signal Transduction - immunology
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1313.040

: Pemphigus is a fatal autoimmune disease in which autoimmunoglobulins PV‐IgG (binding to desmoglein 3) and PF‐IgG (binding to desmoglein 1) in pemphigus vulgaris and pemphigus foliaceus, respectively, cause intraepidermal blisters, cell‐cell separation (acantholysis), and cell death. The mechanism of acantholytic lesion formation has not yet been elucidated. Recently, we have reported that an apoptotic mechanism might be operative in PV‐IgG‐induced acantholysis: (1) in patients' lesional and some perilesional skin portions, the FasR pathway is activated as its components were enriched; (2) in cultured keratinocytes, PV‐IgG upregulates effectors of the FasR pathway (including the mitochondrial loop), as found by immunodetermination (cytochemistry, Western blot of pathway effectors) and determination of caspases 1, 3, and 8/activity/activation; (3) in organ cultures of skin incubated with PV‐IgG, activated caspase 8 was found also in perilesional cells and coaggregated with bound PV‐IgG; (4) caspase 8 activation in DISCs precedes caspase 3 activation in keratinocytes in cultures upon incubation with PV‐IgG. Because caspase activation was shown to accompany lesion formation in cell and organ cultures incubated with PV‐IgG, we used caspase activity to monitor the pathogenicity of PV‐IgG in relation to PV‐IgG binding to epithelia. A rough correlation was found between sera titers, determined by IIF and by immunoblot binding to desmoglein 3, and activation of caspase 3.