(provided by applicatnt): Bullous pemphigoid (BP) are life-threatening blistering diseases that are characterized by the presence of sub-epidermal vesicles and complement-activating autoantibodies directed against the hemidesmosomal proteins, BP180 and BP230. BP autoantibodies are predominant IgG and IgE. Human BP and BP animal model studies have suggested that the key pathogenic elements of these diseases include autoantibody reactivity to BP180, complement, mast cells, and neutrophils/eosinophils. Neutrophil elastase, MMP-9, and plasmin/plasminogen system are directly involved in tissue injury at the basement membrane, resulting in dermal-epidermal junction separation. The long-term goal of this project is to increase our understanding of the pathophysiology and autoimmunity of BP and how it relates to the functions of autoantibodies and proteinases in inflammation and autoimmunity. The objective of this application is to study role of proteolytic enzymes, isotype and subclass of pathogenic BP autoantibodies using the rabbit anti-mBP180 IgG passive transfer model and our newly developed humanized BP180NC16A mouse model.
Aim 1 is to study the role of mast cell proteinases using rabbit anti-mBP180 IgG passive transfer model. Pathogenic rabbit anti-mBP180 IgG antibodies will be injected into mice deficient in different mast cell proteinases. Degradation of BP180 and other key extracellular matrix components by these proteolytic enzymes will be determined.
Aim 2 is to directly test the pathogenic activity of autoantibodies from BP patients'sera in humanized BP180NC16A mice, in which mBP180NC14A is replaced with hBP180NC16A. Pathogenic epitopes and IgG subclasses of human BP autoantibodies will also be identified by using the humanized mice.
Aim 3 is to test whether anti-BP180 IgE autoantibodies and eosinophils play a part in the disease process.
Aim 4 is to test pathogenicity of anti-BP180 autoantibodies from patients with herpes gestationis. Findings from these proposed studies will significantly increase our understanding of the disease mechanisms and help develop more specific and effective and less side-effect therapies for BP patients. Bullous pemphigoid (BP) is the most common and potentially fatal autoimmune blistering disease. Better understanding of the disease process will lead to more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040768-14
Application #
8121535
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Rothermel, Annette L
Project Start
1996-07-01
Project End
2013-05-31
Budget Start
2011-09-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2011
Total Cost
$326,374
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
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
Olivry, Thierry; Dunston, Stanley M; Walker, Robina H et al. (2009) Investigations on the nature and pathogenicity of circulating antikeratinocyte antibodies in dogs with pemphigus foliaceus. Vet Dermatol 20:42-50
Heimbach, L; Li, N; Diaz, A et al. (2009) Experimental animal models of bullous pemphigoid. G Ital Dermatol Venereol 144:423-31
Li, Ning; Zhao, Minglang; Wang, Jinzhao et al. (2009) Involvement of the apoptotic mechanism in pemphigus foliaceus autoimmune injury of the skin. J Immunol 182:711-7

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