Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies and an inflammatory infiltrate at the lesional site. BP autoantibodies recognize two hemidesmosomal proteins, BP180 and BP230. In vitro and in vivo studies have demonstrated that anti-BP180 IgG autoantibodies fix complement and are pathogenic. NC16A, an extracellular domain of BP180, is the primary target of pathogenic autoantibodies. Elevated proinflammatory cytokines including TNF-? and IL-1? are present in blister fluids and sera of BP patients. However, the roles of these critical inflammatory mediators and how they are up-regulated in BP remain unknown. Lack of a suitable in vivo system is a major obstacle for studies of inflammatory immune responses in BP using patient-derived autoantibodies. Our lab recently generated a humanized BP180 mouse strain (termed NC16A mice), in which the mouse BP180NC14A domain is replaced by the human BP180NC16A domain. The NC16A mice injected with anti-NC16A autoantibodies develop skin lesions that recapitulate key immunohistological features of BP. Our preliminary results showed that subepidermal blister formation induced by pathogenic antibodies is associated with and dependent on increased levels of TNF-? and IL-1?, and blocking inflammasome assembly/activation genetically or pharmacologically significantly reduces the IL-1? level and abolishes subsequent blistering. Therefore, the objective of this proposal is to study the role of inflammasomes in BP using our NC16A mouse model. Our central hypothesis for this proposal is that inflammasomes play a critical role in the development of experimental BP by mediating IL-1? generation and subsequent inflammatory cell infiltration and tissue injury. To determine whether inflammasomes are involved in experimental BP and to uncover the precise functions of inflammasomes during the subepidermal blistering formation, we propose the following Specific Aims:
Aim 1 is to determine whether inflammasome activation is required for experimental BP in NC16A mice;
Aim 2 is to determine whether anti-NC16A autoantibody-mediated inflammasome activation takes place in mast cells;
Aim 3 will determine whether inflammasome-independent activation of IL-1? is up-regulated and involved in BP blistering in NC16A mice. The proposed studies seek to establish a direct link between the inflammasome activation and BP, a role which has not been established in BP and any other autoimmune, especially autoantibody-mediated diseases. Since this proposal integrates both disease mechanism studies and preclinical trials, the findings are expected to have a significant impact on the treatment of patients with BP.

Public Health Relevance

Bullous pemphigoid is a potentially fatal autoimmune blistering disease. We will study the autoantibody-mediated inflammatory responses in the skin blistering disease bullous pemphigoid using in vitro and in vivo model systems. Findings from these studies may help identify new targets and develop more effective therapies for bullous pemphigoid and other autoimmune and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040768-16
Application #
8664774
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rothermel, Annette L
Project Start
1996-07-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Dermatology
Type
Schools of Medicine
DUNS #
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
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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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