High-dose intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of a variety of immune-mediated inflammatory diseases. Numerous mechanisms have been proposed to explain the mode of action of IVIG. In this application, we propose to investigate the molecular basis for the protective property of IVIG in the autoimmune blistering diseases pemphigus and pemphigoid. Pemphigus and pemphigoid are a group of potentially fatal organ specific autoimmune diseases. Pemphigus is characterized by intraepidermal blisters and epidermal-specific IgG autoantibodies. Pemphigoid is characterized by subepidermal blisters and autoantibodies against hemidesmosomal and extracellular matrix components in the basement membrane zone (BMZ). In this proposal, we will focus on three clinical entities: pemphigus foliaceus (PF), pemphigus vulgaris (PV), and bullous pemphigoid (BP). We will use well-characterized IgG passive transfer and active animal models for these diseases to test a hypothesis that infused WIG prevents IgG antibody-mediated blistering diseases by binding and blocking FcRn, the protection receptor for IgG catabolism, which leads to accelerated clearance of pathogenic IgG.
In Aim 1, we will determine whether therapeutic doses of IVlG block blisters in experimental PF, PV, BP, and MMP.
In Aim 2, we will determine whether the protective property of IVlG in these disease models depends on FcRn. We will induce skin disease in FcRn-deficient mice with IVIG treatment.
In Aim 3, we will determine whether IgG Fc fragments can replace IVIG and FcRn inhibitory peptides are therapeutic. The overall goal of this project is to study the mechanisms of WIG action in autoantibody-mediated diseases and develop novel therapies to replace current immunosuppressive treatments, which confer severe side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061430-03
Application #
7050144
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Rothermel, Annette L
Project Start
2004-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$320,781
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
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
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
Liu, Zhi; Sui, Wen; Zhao, Minglang et al. (2008) Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun 31:331-8
Lessey, Elizabeth; Li, Ning; Diaz, Luis et al. (2008) Complement and cutaneous autoimmune blistering diseases. Immunol Res 41:223-32
Leighty, Lisa; Li, Ning; Diaz, Luis A et al. (2007) Experimental models for the autoimmune and inflammatory blistering disease, Bullous pemphigoid. Arch Dermatol Res 299:417-22
Chen, Mei; Doostan, Arvin; Bandyopadhyay, Pubali et al. (2007) The cartilage matrix protein subdomain of type VII collagen is pathogenic for epidermolysis bullosa acquisita. Am J Pathol 170:2009-18
Liu, Zhi; Li, Ning; Diaz, Luis A (2006) Inhibition of pemphigus vulgaris by targeting of the CD40-CD154 co-stimulatory pathway: a step toward antigen-specific therapy? J Invest Dermatol 126:11-3

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