Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin
Open Access
- 20 May 2022
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Immunology
- Vol. 13, 884067
- https://doi.org/10.3389/fimmu.2022.884067
Abstract
Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg) 1 and Dsg 3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human ex vivo skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca2+ to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca2+) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft
This publication has 200 references indexed in Scilit:
- Mechanistic Basis of Desmosome-Targeted DiseasesJournal of Molecular Biology, 2013
- DSG3 Facilitates Cancer Cell Growth and Invasion through the DSG3-Plakoglobin-TCF/LEF-Myc/Cyclin D1/MMP Signaling PathwayPLOS ONE, 2013
- Desmoplakin Regulates Desmosome HyperadhesionJournal of Investigative Dermatology, 2012
- An Adult Passive Transfer Mouse Model to Study Desmoglein 3 Signaling in Pemphigus VulgarisJournal of Investigative Dermatology, 2012
- The Extent of Desmoglein 3 Depletion in Pemphigus Vulgaris Is Dependent on Ca2+-Induced Differentiation: A Role in Suprabasal Epidermal Skin Splitting?The American Journal of Pathology, 2011
- Desmosome Disassembly in Response to Pemphigus Vulgaris IgG Occurs in Distinct Phases and Can Be Reversed by Expression of Exogenous Dsg3Journal of Investigative Dermatology, 2011
- The Extracellular Architecture of Adherens Junctions Revealed by Crystal Structures of Type I CadherinsStructure, 2011
- A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene Underlies Hereditary Hypotrichosis and Recurrent Skin VesiclesAmerican Journal of Human Genetics, 2009
- Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: A paradigm of human autoimmunityJournal of Autoimmunity, 2008
- The desmosome and pemphigusHistochemistry and Cell Biology, 2008