Bullous Pemphigoid (BP) and herpes gestationis (HG) are life-threatening blistering diseases that are characterized by the production of autoantibodies directed against the hemidesmosomal proteins, BPl80 and BP230, and by itie formation of subepidermal vesicles. The overall goal of this project is to advance our understanding of the immunopathological mechanisms operating in these diseases. The major focus of the present proposal is to test the hypothesis that the destruction of the dermal-epidermal junction is caused by proleolytic enzymes released from infiltrating inflammatory cells.
Specific aims 1 and 2 are to further dissect the mechanism of recruitment and activation of neutrophils (i.e. the role of cell adhesion molecules and cell surface receptors) and investigate the possible role of eosinophils in subepidermal blistering. Passive transfer experiments with pathogenic anti-BP180 IgG will be performed on mice deficient in proinflammatory cytokines, neutrophil migration-related integrins or activation-related Fc receptors. The role of eosinophils will be investigated by depletion and reconstitution experiments.
Specific aim 3 is designed to determine the role of proteolytic enzymes and the reactive oxidants in experimental BP and HG and test the hypothesis that degradation products of BPl80 are chemotactic. Mice deficient in these proteinases will be injected with pathogenic IgG. The chemotactic activity of the BPl80 fragments will be tested by in vitro and in vivo chemotaxis assays.
Specific aim 4 is to study effects and mechanisms of action of anti-inflammatory drugs in subepidermal blistering using passive transfer experiments and pharmacologic approaches.
Specific aim 5 is to develop a novel system to directly test the pathogenic activity of autoantibodies from BP and HG patients' sera. These autoantibodies will be injected into neonatal transgenic mice expressing human BPl80 in the basal keratinocytes. Affinity-purified autoantibodies against specific antigenic sites on human BPl80 will also be used in this in viva system to map the pathogenic epitopes). The results from these studies will have profound clinical implications in the care of patients with BP and HG and other related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040768-08
Application #
6608189
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Rothermel, Annette L
Project Start
1996-07-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
8
Fiscal Year
2003
Total Cost
$254,625
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Dermatology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Fang, Hui; Zhang, Yang; Li, Ning et al. (2018) The Autoimmune Skin Disease Bullous Pemphigoid: The Role of Mast Cells in Autoantibody-Induced Tissue Injury. Front Immunol 9:407
Evangelista, Flor; Roth, Aleeza J; Prisayanh, Phillip et al. (2018) Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope. J Autoimmun 89:171-185
Zhang, Yang; Hwang, Bin-Jin; Liu, Zhen et al. (2018) BP180 dysfunction triggers spontaneous skin inflammation in mice. Proc Natl Acad Sci U S A 115:6434-6439
Li, Ning; Park, Moonhee; Xiao, Shengxiang et al. (2017) ER-to-Golgi blockade of nascent desmosomal cadherins in SERCA2-inhibited keratinocytes: Implications for Darier's disease. Traffic 18:232-241
Zuo, Yagang; Evangelista, Flor; Culton, Donna et al. (2016) IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid. J Autoimmun 73:111-9
Wang, Xue; Chen, Tiancheng; Zhao, Junyu et al. (2016) Extremities of the N-terminus of envoplakin and C-terminus of its linker subdomain are major epitopes of paraneoplastic pemphigus. J Dermatol Sci 84:24-29
Lin, Lan; Betsuyaku, Tomoko; Heimbach, Lisa et al. (2012) Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid. Matrix Biol 31:38-44
Heimbach, Lisa; Li, Zhuowei; Berkowitz, Paula et al. (2011) The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid. J Biol Chem 286:15003-9
Lin, Lan; Bankaitis, Eric; Heimbach, Lisa et al. (2011) Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid. J Biol Chem 286:37358-67
Li, Ning; Park, Moonhee; Zhao, Minglang et al. (2010) The Thomsen-Friedenreich antigen-binding lectin jacalin interacts with desmoglein-1 and abrogates the pathogenicity of pemphigus foliaceus autoantibodies in vivo. J Invest Dermatol 130:2773-80

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