Pemphigus IgG Internalization and Desmosome Disassembly

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
Pemphigus vulgaris (PV) is a severe autoimmune blistering disease characterized by the disruption of adhesion between epithelial cells in the oral mucosa and in the lower layers of the epidermis. The antigen targeted by autoantibodies in this disease is the desmosomal cadherin desmoglein-3 (Dsg3). Desmosomes are cell-cell adhesion structures that play critical roles in the establishment and maintenance of epidermal integrity. A major consequence of Dsg3 autoantibody production is the disruption of desmosomal cell-cell adhesion, and it is likely that PV antibodies directly interfere with cell-cell adhesion mediated by Dsg3. However, numerous studies have also demonstrated that desmosomal components are internalized by keratinocytes exposed to PV sera, both in vivo and in vitro. In preliminary studies, we have found that PV sera as well as pathogenic monoclonal antibodies directed against Dsg3 are internalized by keratinocytes and enter the endocytic pathway. These observations raise the possibility that endocytosis of Dsg3 leads to a significant reduction of cell surface levels of Dsg3, and that Dsg3 internalization in response to PV antibodies may be causally related to pemphigus disease pathogenesis. Therefore, by inhibiting Dsg3 endocytosis in response to PV IgG ligation, it might be possible to blunt the impact ofPV autoantibodies on epithelial cellcell adhesion. In order to address this possibility, a sophisticated understanding of how membrane trafficking systems interface with desmosomal adhesion molecules is needed. This R21 proposal will test the hypothesis that pathogenic Dsg3 antibodies cause the internalization of this cell surface adhesion molecule. Two aims are proposed. First, we will establish as series of quantitative assays to monitor PV IgG internalization, and use these assays in combination with pharmacological and dominant negative approaches to determine the basic mechanisms by which Dsg3 is internalized. Secondly, we will determine if PV IgG and Dsg3 are internalized alone, or as a complex with other desmosomal molecules. We will then test the possibility that components of the desmosome regulate Dsg3 internalization. These experiments will form the foundation for a subsequent R01 application. The long-term goal of these studies is to expose new cellular pathways that might be targeted therapeutically to make keratinocytes more resistant to PV IgG in patients suffering from this devastating disease.
StatusFinished
Effective start/end date9/30/035/31/06

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $153,000.00
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $153,000.00

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