title: Mechanisms of mitochondrial damage in keratinocytes by pemphigus vulgaris antibodies.
abstract: The development of nonhormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species. Indeed, measurement of intracellular reactive oxygen species production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. Although sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide (also called niacinamide), minocycline, and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized nonhormonal therapies of patients with this potentially lethal autoimmune blistering disease.
authors.affiliation: Departments of Dermatology, Irvine, California 92697.
authors.forename: Mina
authors.initials: M
authors.lastname: Kalantari-Dehaghi
authors.affiliation: Medicine, Irvine, California 92697.
authors.forename: Yumay
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Medicine, Irvine, California 92697.
authors.forename: Wu
authors.initials: W
authors.lastname: Deng
authors.affiliation: Departments of Dermatology, Irvine, California 92697.
authors.forename: Alex
authors.initials: A
authors.lastname: Chernyavsky
authors.affiliation: Departments of Dermatology, Irvine, California 92697.
authors.forename: Steve
authors.initials: S
authors.lastname: Marchenko
authors.affiliation: Medicine, Irvine, California 92697; Biological Chemistry, Irvine, California 92697. Electronic address: phwang@uci.edu.
authors.forename: Ping H
authors.initials: PH
authors.lastname: Wang
authors.affiliation: Departments of Dermatology, Irvine, California 92697; Biological Chemistry, Irvine, California 92697; Institute for Immunology, University of California, Irvine, California 92697. Electronic address: sgrando@uci.edu.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002461:Cell Line, Transformed; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008911:Minocycline / Q000494:pharmacology; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects / Q000276:immunology; D010392:Pemphigus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001323:Autoantibodies; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D014803:Vitamin B Complex; D009536:Niacinamide; D016572:Cyclosporine; D008911:Minocycline
keywords: Animal Models; Autoimmune Diseases; Mitochondria; Pemphigus; Skin