The Mechanism of IVIG Action in Pemphigus

Summary

Principal Investigator: Zhi Liu
Abstract: 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.
Funding Period: 2004-05-01 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Role of FcRs in animal model of autoimmune bullous pemphigoid
    Minglang Zhao
    Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill 27599, USA
    J Immunol 177:3398-405. 2006
  2. pmc Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid
    Lan Lin
    Dalian University of Technology, Dalian, Liaoning, P R China Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA
    Matrix Biol 31:38-44. 2012
  3. pmc Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid
    Lan Lin
    School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024 Liaoning, China
    J Biol Chem 286:37358-67. 2011
  4. pmc The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid
    Lisa Heimbach
    Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Biol Chem 286:15003-9. 2011
  5. pmc The Thomsen-Friedenreich antigen-binding lectin jacalin interacts with desmoglein-1 and abrogates the pathogenicity of pemphigus foliaceus autoantibodies in vivo
    Ning Li
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Invest Dermatol 130:2773-80. 2010
  6. pmc Involvement of the apoptotic mechanism in pemphigus foliaceus autoimmune injury of the skin
    Ning Li
    Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA
    J Immunol 182:711-7. 2009
  7. pmc Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model
    Zhi Liu
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Autoimmun 31:331-8. 2008
  8. ncbi Complement and cutaneous autoimmune blistering diseases
    Elizabeth Lessey
    Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA
    Immunol Res 41:223-32. 2008
  9. pmc Experimental models for the autoimmune and inflammatory blistering disease, Bullous pemphigoid
    Lisa Leighty
    Department of Dermatology, University of North Carolina School of Medicine, 3100 Thurston Bowles, Chapel Hill, NC 27599, USA
    Arch Dermatol Res 299:417-22. 2007
  10. pmc The cartilage matrix protein subdomain of type VII collagen is pathogenic for epidermolysis bullosa acquisita
    Mei Chen
    Department of Dermatology, The Keck School of Medicine, University of Southern California, 1303 Mission Road, Los Angeles, CA 90033, USA
    Am J Pathol 170:2009-18. 2007

Scientific Experts

  • Zhi Liu
  • Ning Li
  • Mei Chen
  • Luis A Diaz
  • Lan Lin
  • Lisa Heimbach
  • Minglang Zhao
  • Lijia An
  • Steven D Shapiro
  • Elizabeth Lessey
  • Lisa Leighty
  • Kelly C Nelson
  • David Rubenstein
  • Robert M Senior
  • Tomoko Betsuyaku
  • George J Giudice
  • Zena Werb
  • Paula Berkowitz
  • Eric Bankaitis
  • David S Rubenstein
  • Zhuowei Li
  • Magnus Abrink
  • Gunnar Pejler
  • Luis Diaz
  • Mary E Trimbeger
  • Pamela R Schroeder
  • Rick A Wetsel

Detail Information

Publications15

  1. ncbi Role of FcRs in animal model of autoimmune bullous pemphigoid
    Minglang Zhao
    Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill 27599, USA
    J Immunol 177:3398-405. 2006
    ..Results from this study establish that Fc gammaRIII plays a critical role in the activation of infiltrating neutrophils and the subsequent blistering in experimental BP...
  2. pmc Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid
    Lan Lin
    Dalian University of Technology, Dalian, Liaoning, P R China Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA
    Matrix Biol 31:38-44. 2012
    ..These results demonstrate that (i) NE directly damages the extracellular matrix and (ii) NE degradation of mouse BP180 generates neutrophil chemotactic peptides that amplify disease severity at the early stage of the disease...
  3. pmc Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid
    Lan Lin
    School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024 Liaoning, China
    J Biol Chem 286:37358-67. 2011
    ....
  4. pmc The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid
    Lisa Heimbach
    Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Biol Chem 286:15003-9. 2011
    ..Taken together, these data demonstrate that C5a interacts with C5aR on MCs and that this C5a-C5aR interaction triggers activation of the p38 MAPK pathway, subsequent MC degranulation, and ultimately BP blistering...
  5. pmc The Thomsen-Friedenreich antigen-binding lectin jacalin interacts with desmoglein-1 and abrogates the pathogenicity of pemphigus foliaceus autoantibodies in vivo
    Ning Li
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Invest Dermatol 130:2773-80. 2010
    ..TF-specific binding ligands may have a potential therapeutic value for PF...
  6. pmc Involvement of the apoptotic mechanism in pemphigus foliaceus autoimmune injury of the skin
    Ning Li
    Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA
    J Immunol 182:711-7. 2009
    ..Collectively, these findings show that biochemical events of apoptosis are provoked in the epidermis of mice injected with PF autoantibodies. Caspase activation may contribute to acantholytic blister formation in PF...
  7. pmc Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model
    Zhi Liu
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Autoimmun 31:331-8. 2008
    ..The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players...
  8. ncbi Complement and cutaneous autoimmune blistering diseases
    Elizabeth Lessey
    Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA
    Immunol Res 41:223-32. 2008
    ....
  9. pmc Experimental models for the autoimmune and inflammatory blistering disease, Bullous pemphigoid
    Lisa Leighty
    Department of Dermatology, University of North Carolina School of Medicine, 3100 Thurston Bowles, Chapel Hill, NC 27599, USA
    Arch Dermatol Res 299:417-22. 2007
    ..The development of two novel humanized mouse models for the first time has enabled study of disease mechanisms caused by BP autoantibodies, and presents an ideal in vivo system to test novel therapeutic strategies for disease management...
  10. pmc The cartilage matrix protein subdomain of type VII collagen is pathogenic for epidermolysis bullosa acquisita
    Mei Chen
    Department of Dermatology, The Keck School of Medicine, University of Southern California, 1303 Mission Road, Los Angeles, CA 90033, USA
    Am J Pathol 170:2009-18. 2007
    ..This is the first antigenic epitope on type VII collagen demonstrated to be a pathogenic target for EBA autoantibodies...
  11. pmc Role of different pathways of the complement cascade in experimental bullous pemphigoid
    Kelly C Nelson
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Clin Invest 116:2892-900. 2006
    ..These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP...
  12. ncbi Inhibition of pemphigus vulgaris by targeting of the CD40-CD154 co-stimulatory pathway: a step toward antigen-specific therapy?
    Zhi Liu
    Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Invest Dermatol 126:11-3. 2006
    ..Thus, blockade of this ligand-receptor interaction can prevent the development of antibody-mediated autoimmune diseases through different mechanisms...
  13. pmc Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases
    Ning Li
    Department of Dermatology, University of North Carolina at Chapel Hill, North Carolina 27599, USA
    J Clin Invest 115:3440-50. 2005
    ..These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases...
  14. pmc Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid
    Zhi Liu
    Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599, USA
    Blood 107:1063-9. 2006
    ..These data suggest that beta2 integrins play differential roles in experimental BP: LFA-1 is required for neutrophil recruitment, while Mac-1 mediates late neutrophil accumulation and apoptosis of infiltrating neutrophils...
  15. pmc Synergy between a plasminogen cascade and MMP-9 in autoimmune disease
    Zhi Liu
    Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Clin Invest 115:879-87. 2005
    ..Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP...