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.
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.
Frusic-Zlotkin
Marina
M
Life Sciences Institute, Campus Edmond Safra, Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Pergamentz
Rochel
R
Michel
Beno
B
David
Michael
M
Mimouni
Daniel
D
Brégégère
François
F
Milner
Yoram
Y
D000051:Acantholysis / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D004817:Epidermis / Q000276:immunology*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007074:Immunoglobulin G; D015603:Keratinocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D009924:Organ Culture Techniques; D010392:Pemphigus / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D001323:Autoantibodies; D061945:Caspase Inhibitors; D007074:Immunoglobulin G; D020169:Caspases