This competitive renewal of the R01 AR 32599 is aimed at discovering the etiology of endemic pemphigus foliaceus (PF), also known as Fogo Selvagem (FS). Some of the advantages that an organ-specific autoimmune disease such as FS (which is epidermal-specific) offers to research in autoimmunity are related to the fact that anti-Dsg1 (desmoglein 1) autoantibodies are pathogenic and the self-antigen, Dsg1, is fully characterized. The Amerindian reservation of Limao Verde, located in the state of Mato Grosso do Sul, Brazil, is the home of 1,351 members of the Terena tribe of Amerindians (as of September 10, 2006), and is an active focus of FS, exhibiting a ~3 percent prevalence of disease. For the last 12 years, we have systematically collected clinical and serological data from FS patients, as well as clinically normal individuals residing in and around this settlement. Anti-Dsg1 autoantibodies in healthy individuals from LV and neighboring communities are common, and directly related to proximity to this reservation. We have also observed the clinical and serological conversion from normal to disease state in 11 individuals. This transition was heralded from non-pathogenic IgG autoantibodies targeting the EC5 domain of Dsg1 during the pre-clinical stage to a pathogenic IgG response against the Dsg1 EC1-2 domains during the onset of clinically active disease. We have also reported that the pathogenic antibodies are IgG4 restricted. We have recently found that the IgM anti-Dsg1 autoantibody response is distinctive to FS patients exposed to their native rural environment, marker that is not prevalent in other forms of pemphigus. This novel autoantibody is also detected in clinically normal individuals living in LV and its neighboring rural regions since early childhood, being absent in neonates. Two prong approaches, i.e. epidemiological and immunological are utilized to explore the central hypothesis of the grant that states that an environmental antigen(s), i.e., hematophagous insect bites sensitize individuals living in Limao Verde. We believe that both approaches are not exclusive but complementary to each other. The immunological methodologies will yield new immunological assays and instruments that will facilitate the identification of individuals at risk to develop FS. For example, based on the assessment of IgG subclass anti- Dsg1 antibodies in a large set of FS and controls we have developed an """"""""IgG4 classifier/predictor,"""""""" which is highly sensitive and specific. This instrument defines a serum as having serological features of FS (pre-clinical stage) or features of a healthy individual. Using this new """"""""IgG4 classifier/predictor"""""""" we have analyzed the sera of 96 members of 3 cohorts from Limao Verde and have identified 21 individuals with serological features of FS and 75 with features of healthy controls (samples collected in 2005). These individual at risk to develop FS will be HLA-typed and are under close surveillance for any evidence of clinical FS. Completion of the aims of this project will benefit our understanding of human autoimmune diseases seen in the USA and around the world. Narrative: The grant R01 AR32599 is aimed at disclosing the etiology of a human autoimmune skin disease, endemic pemphigus foliaceus, which is endemic in Brazil. At the completion of this application we will have a better understanding of other human autoimmune diseases like lupus erythematosus, rheumatoid arthritis, thyroiditis, and others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032599-30
Application #
8243470
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
1988-07-01
Project End
2013-09-15
Budget Start
2012-04-01
Budget End
2013-09-15
Support Year
30
Fiscal Year
2012
Total Cost
$295,650
Indirect Cost
$86,562
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
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
Maldonado, Mike; Diaz, Luis A; Prisayanh, Phillip et al. (2017) Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem). Immunohorizons 1:71-80
Boyden, Lynn M; Vincent, Nicholas G; Zhou, Jing et al. (2017) Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet 100:978-984
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
Qian, Ye; Jeong, Joseph S; Ye, Jian et al. (2016) Overlapping IgG4 Responses to Self- and Environmental Antigens in Endemic Pemphigus Foliaceus. J Immunol 196:2041-50
Qian, Ye; Culton, Donna A; Jeong, Joseph S et al. (2016) Non-infectious environmental antigens as a trigger for the initiation of an autoimmune skin disease. Autoimmun Rev 15:923-30
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
Aoki, Valeria; Rivitti, Evandro A; Diaz, Luis A et al. (2015) Update on fogo selvagem, an endemic form of pemphigus foliaceus. J Dermatol 42:18-26
Qian, Ye; Jeong, Joseph S; Abdeladhim, Maha et al. (2015) IgE anti-LJM11 sand fly salivary antigen may herald the onset of fogo selvagem in endemic Brazilian regions. J Invest Dermatol 135:913-915

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