This is a revised version of the RO1 AR32081-25 which tests the hypothesis that the autoantibody response in humans against desmoglein 1 (Dsg1) and Dsg3 is diverse, ranging from a non-pathogenic and persistent response detected in normal individuals to a frankly pathogenic reaction found in pemphigus vulgaris (PV) and pemphigus foliaceus/fogo selvagem (PF/FS) patients. The skin phenotype in normal and diseased individuals is driven by the epitope specificity of these autoantibodies. It is predicted that phenomena such as epitope cross-reactivity and epitope spreading are feasible in individuals with the appropriate genetic background due to the extensive homology between Dsg1 and Dsg3. This hypothesis explains the prevalence of non-pathogenic and pathogenic anti-Dsgl and anti-Dsg3 autoantibodies in patients and normal individuals, the rare transition of phenotype from PV to PF or PF to PV and the existence of a novel form of """"""""endemic PV"""""""" in endemic regions of FS in Brazil. We are interested on determining the fine epitope specificity and the IgG subclass restriction of anti-Dsgl and anti-Dsg3 autoantibodies during the progression of the autoimmune response from normal, pre-clinical and clinical stages of PV and PF/FS. Our studies show that conversion from non-pathogenic anti-Dsgl response (found in normal individuals with anti-EC5 domain) to pathogenic (found in FS patients) is linked to the emergence of population of anti-Ed-2 autoantibodies to this antigen. These projects are facilitated by our unique bank of sera from PV, non-endemic PF, FS and normal donors, which include patients in different stages of disease evolution. We describe exciting novel, unreported studies that stern out of the aims of this grant, e.g. the high frequency and distinctive presence of anti-Dsgl IgM autoantibodies in FS and the presence of anti-E cadherin autoantibodies in PV, PF/FS to name two. We have also characterized several B cell clones from PV, PF and FS and sequenced the IgG V region genes and began to explore the diversity of the autoimmune response in these patients. Similarly, we have also generated human/mouse IgM monoclonal antibodies, which will be further analyzed for V gene diversity. Finally, we will generate human anti-idiotypic antibodies by phage display technology and attempt to block binding of PV or PF/FS autoantibodies to their target epidermal antigens, thus preventing disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032081-29
Application #
8126237
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
1988-07-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
29
Fiscal Year
2011
Total Cost
$292,364
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
Culton, Donna A; McCray, Suzanne K; Park, Moonhee et al. (2015) Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice. J Invest Dermatol 135:1590-1597
Oliveira, M E F; Culton, D A; Prisayanh, P et al. (2013) E-cadherin autoantibody profile in patients with pemphigus vulgaris. Br J Dermatol 169:812-8
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
Culton, Donna A; Diaz, Luis A (2012) Treatment of subepidermal immunobullous diseases. Clin Dermatol 30:95-102
Flores, Gustavo; Culton, Donna A; Prisayanh, Phillip et al. (2012) IgG autoantibody response against keratinocyte cadherins in endemic pemphigus foliaceus (fogo selvagem). J Invest Dermatol 132:2573-80
Qian, Ye; Jeong, Joseph S; Maldonado, Mike et al. (2012) Cutting Edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen. J Immunol 189:1535-9
James, Kirk A; Culton, Donna A; Diaz, Luis A (2011) Diagnosis and clinical features of pemphigus foliaceus. Dermatol Clin 29:405-12, viii
Qian, Ye; Prisayanh, Phillip; Andraca, Eugenio et al. (2011) IgE, IgM, and IgG4 anti-desmoglein 1 autoantibody profile in endemic pemphigus foliaceus (fogo selvagem). J Invest Dermatol 131:985-7
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

Showing the most recent 10 out of 59 publications