Pathogenicity and Epitope Specificity of IgG4 Autoantibodies in Endemic Pemphigus Foliaceus
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Evangelista Montoya, Flor De Maria. Pathogenicity and Epitope Specificity of Igg4 Autoantibodies In Endemic Pemphigus Foliaceus. University of North Carolina at Chapel Hill, 2012. https://doi.org/10.17615/0fsg-zg24APA
Evangelista Montoya, F. (2012). Pathogenicity and Epitope Specificity of IgG4 Autoantibodies in Endemic Pemphigus Foliaceus. University of North Carolina at Chapel Hill. https://doi.org/10.17615/0fsg-zg24Chicago
Evangelista Montoya, Flor De Maria. 2012. Pathogenicity and Epitope Specificity of Igg4 Autoantibodies In Endemic Pemphigus Foliaceus. University of North Carolina at Chapel Hill. https://doi.org/10.17615/0fsg-zg24- Last Modified
- March 22, 2019
- Creator
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Evangelista Montoya, Flor de Maria
- Affiliation: School of Medicine, Department of Microbiology and Immunology
- Abstract
- Endemic pemphigus foliaceus, also known as Fogo Selvagem (FS), is an autoimmune blistering skin disease that exhibits geographic clustering and 100% mortality without treatment. An active focus of FS is located in the rural reservation of Limao Verde (LV), Mato Grosso do Sul, Brazil. It is widely accepted that the autoantibodies that mediate FS are predominantly of the IgG4 subclass against Desmoglein 1 (Dsg1) and that healthy individuals living in LV posses a mixture of circulating IgG anti-Dsg1 autoantibodies. It has been suggested that an unknown environmental trigger present in LV may induce an anti-Dsg1 autoimmune response, which in certain genetically predisposed individuals leads to a pathogenic IgG4 response and clinical disease. The transition from preclinical to clinical disease in FS has been associated with subclass switching and epitope spreading within the extracellular domain of Dsg1. The N-terminal region of Dsg1 has been reported to be the target for pathogenic FS IgG autoantibodies. However, the fine epitope specificity for FS IgG4 autoantibodies remains unknown. The work in this dissertation refines the identification of epitopes in Dsg1 that are recognized specifically by IgG4 autoantibodies from FS patients. Two dominant conformational epitopes were identified using epitope excision and MALDI-MS/MS. One epitope was located within the EC1 domain of Dsg1 (A129-R144) and the second epitope in the EC2 domain (Q201-R213). Moreover, residues M133 and Q135 are required to achieve the proper conformation of the epitope recognized by pathogenic IgG4 autoantibodies in FS. This study also reports that IgG4 FS antibodies recognize LJM11, a protein found in the saliva of Lutzomya longipalpis. In addition, mice immunized with LJM11 generate anti-Dsg1 antibodies. Thus, insect bites may deliver salivary antigens that initiate a cross-reactive IgG4 autoimmune response in genetically susceptible individuals, which subsequently leads to development of FS. The findings of this dissertation may uncover targets such as the epitope in EC1 for the development of epitope-specific preventative and therapeutic strategies. Additionally, this work identifies an environmental, non-infectious antigen, which may trigger development of potentially pathogenic autoantibodies in autoimmune disease.
- Date of publication
- May 2012
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- In Copyright
- Advisor
- Liu, Zhi
- Degree
- Doctor of Philosophy
- Graduation year
- 2012
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