Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies and an inflammatory infiltrate at the lesional site. BP autoantibodies belong to IgG and IgE isotypes and recognize two hemidesmosomal proteins, BP180 and BP230. These autoantibodies mainly target the NC16A extracellular domain of BP180. The dermal infiltrate contains eosinophils, neutrophils, mast cells, macrophage and lymphocytes, with eosinophils being the predominant cell type. The roles of anti-BP180 IgG autoantibodies and neutrophils in BP have been extensively investigated. In vitro and in vivo studies have demonstrated that anti-BP180 NC16A IgG autoantibodies fix complement, recruit neutrophils and cause BP-like blisters. However, roles of anti-BP180 IgE and eosinophils in BP remain largely unknown. Lack of a suitable animal model is a major obstacle for studies of IgE and eosinophils because human IgE do not recognize mouse IgE receptors. Our lab currently developed a double humanized mouse stain (termed hFc?RI/NC16A mice), in which the human NC16A domain replaced the mouse counterpart NC14A domain and human Fc?RI are expressed on eosinophils and mast cells. More significantly, adult hFc?RI/NC16A mice injected with anti- NC16A IgE autoantibodies from BP patients develop BP skin disease that required eosinophils and mast cells. The objective of this proposal is to study the role of eosinophils and mast cells in BP using our newly developed hFc?RI/NC16A mouse model. The overall goal of this project is to increase our understanding of the innate immunity of BP and how it relates to the functions of innate immune system players in inflammation and autoimmunity. In this grant proposal, we will determine how eosinophils are recruited and functionally interact with mast cells (Aims 1 and 2). Proteolytic enzymes from these innate immune cells are critical for skin tissue injury, therefore, we will translate our animal model findings to human BP (Aim 3). 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 (BP) is the most common and potentially fatal autoimmune blistering disease associated with inflammation. In this grant application, we propose to study the role of eosinophils in the disease development and identify new targets for more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR070276-01A1
Application #
9383739
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2017-07-24
Project End
2022-06-30
Budget Start
2017-07-24
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
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