Possible apoptotic mechanism in epidermal cell acantholysis induced by pemphigus vulgaris autoimmunoglobulins.
Through a still unclear mechanism, pemphigus vulgaris autoantibodies (PV-IgG) induce intra-epidermal acantholytic lesions responsible for severe to fatal skin wounding. We present evidence that PV lesions contain apoptotic keratinocytes, and that cell death is induced in the lesional tissue apparently before cell separation. These data suggest that apoptosis could be the cause of the acantholytic phenomenon. We show that PV-IgG and an antibody against Fas receptor (anti-FasR) induce lesions in vitro in a similar way, causing: (1) secretion of soluble FasL; (2) elevated cellular amounts of FasR, FasL (soluble and membranal), Bax and p53 proteins; (3) reduction in levels of cellular Bcl-2; (4) enrichment in caspase 8, and activation of caspases 1 and 3; (5) co-aggregation of FasL and FasR with caspase 8 in membranal death-inducing signaling complex (DISC). Hence, the Fas-mediated death signaling pathway seems to be involved in lesion formation. Moreover, we have shown that in skin organ cultures and in keratinocyte cultures, PV-IgG can induce caspase activation and DNA fragmentation, and caspase inhibitors can prevent the formation of PV-IgG-induced epidermal lesions. Altogether, these results suggest that PV-IgG-induced acantholysis may proceed through the death-signaling pathway. They highlight new perspectives on mechanisms of tissue damage in autoimmune diseases.
Department of Biological Chemistry, Myers Skin Biology and Biochemistry Laboratory, The Hebrew University, Givat Ram, Jerusalem, Israel.
X
X
Wang
F
F
Brégégère
M
M
Frusić-Zlotkin
M
M
Feinmesser
B
B
Michel
Y
Y
Milner
D000051:Acantholysis / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D004817:Epidermis / Q000276:immunology*; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D010392:Pemphigus / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D001323:Autoantibodies; D061945:Caspase Inhibitors; D020169:Caspases