Pemphigus is a class of devastating epidermal blistering diseases in which autoantibodies are generated against cell-cell adhesion molecules present in the skin and mucous membranes. Pemphigus IgG target desmosomes, a structure that couples the keratin intermediate filament network to regions of strong cell-cell adhesion. In pemphigus vulgaris (PV), the primary target of the autoantibodies is desmoglein-3 (Dsg3), a member of the desmosomal cadherin subfamily of adhesion molecules. The work outlined in this application investigates the mechanisms by which IgG from pemphigus vulgaris patients disrupts cell-cell adhesion. It is hypothesized that PV IgG disrupt desmosomes by causing Dsg3 internalization from the cell surface, leading to desmosome destabilization and loss of keratinocyte adhesion. This hypothesis will be tested using a series of in vitro cell culture models that employ cellular and molecular approaches to define the mechanisms by which PV IgG cause Dsg3 internalization and desmosome disassembly. These studies will reveal the cellular machinery and pathways that mediate Dsg3 endocytosis, and how cytoplasmic components of the desmosome regulate Dsg3 internalization. Furthermore, a panel of antibody reagents will be employed, including PV patient IgG, human monoclonal antibodies cloned from patients, and mouse monoclonal Dsg3 antibodies with varying degrees of pathogenic activity. These reagents will be used to reveal relationships between desmosome disassembly pathways and antibody pathogenicity profiles to determine how pemphigus IgG causes disease at the cellular level.

Public Health Relevance

These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of pemphigus and other skin diseases characterized by epidermal fragility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048266-10
Application #
8303018
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2002-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$324,086
Indirect Cost
$114,998
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Stahley, Sara N; Saito, Masataka; Faundez, Victor et al. (2014) Desmosome assembly and disassembly are membrane raft-dependent. PLoS One 9:e87809
Tucker, Dana K; Stahley, Sara N; Kowalczyk, Andrew P (2014) Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes. J Invest Dermatol 134:1033-43
Kowalczyk, Andrew P; Green, Kathleen J (2013) Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 116:95-118
Jennings, Jean M; Tucker, Dana K; Kottke, Margaret D et al. (2011) Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3. J Invest Dermatol 131:706-18
Delva, Emmanuella; Tucker, Dana K; Kowalczyk, Andrew P (2009) The desmosome. Cold Spring Harb Perspect Biol 1:a002543
Delva, Emmanuella; Kowalczyk, Andrew P (2009) Regulation of cadherin trafficking. Traffic 10:259-67
Delva, Emmanuella; Jennings, Jean Marie; Calkins, Catharine C et al. (2008) Pemphigus vulgaris IgG-induced desmoglein-3 endocytosis and desmosomal disassembly are mediated by a clathrin- and dynamin-independent mechanism. J Biol Chem 283:18303-13
Xiao, Kanyan; Oas, Rebecca G; Chiasson, Christine M et al. (2007) Role of p120-catenin in cadherin trafficking. Biochim Biophys Acta 1773:8-16
Calkins, Catharine C; Setzer, Shannon V; Jennings, Jean Marie et al. (2006) Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. J Biol Chem 281:7623-34
Kottke, Margaret D; Delva, Emmanuella; Kowalczyk, Andrew P (2006) The desmosome: cell science lessons from human diseases. J Cell Sci 119:797-806

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