In this project we seek to understand the etiological role of IgE response to environmental antigens in development of an endemic pemphigus foliaceus (PF), Fogo Selvagem (FS). Pemphigus foliaceus represents autoimmune blistering diseases exhibiting pathogenic IgG4 autoantibodies against desmogleins 1 (Dsg1), a desmosomal cell adhesion molecule. Interestingly, there is a well-known sequential development of IgE and IgG4 antibody development during chronic allergen stimulation or during the immunotherapy of allergic diseases. Our latest investigations into IgE antibody response in FS provide evidence that the development of IgG4 antibodies in endemic pemphigus foliaceus is linked to the IgE response to environmental antigens. This evidence includes, but is not limited to: 1) Insect bite is a risk factor for FS. 2) Leishmaniasis and Chaga disease are clustered in FS endemic regions and the vectors for these diseases, such as sand flies, reduviid bugs, and black flies, are also prevalent. Patients with Leishmaniasis and Chagas disease have high levels of anti-Dsg1 antibodies. 3) Insect bites are known to induce IgE response. 4) Significant higher levels of IgE antibodies are present in FS patients, the levels of these IgE antibodies significantly correlating with that of IgG4 antibodies in FS. 5) Monoclonal autoantibodies from FS patients cross-react with LJM11, the most immunogenic component of sand fly salivary gland antigens and a marker for human exposer to sand fly bites. We hypothesize that chronic environmental antigen stimulation in genetic susceptible individuals in FS endemic regions triggers the initial IgE response which leads to the subsequent development of autoantibodies and clinical FS in FS susceptible individuals.
Three aims are proposed in this investigation in order to test our hypothesis. 1) The first aim of this investigaton will focus on the IgE development in FS patients. We will identify whether there is an association between IgE antibodies directed against environmental antigen LJM11 autoantigen and Dsg1 in FS. 2) In the second aim IgE antibodies development in individuals before their onset of clinical FS (pre-FS) and normal individuals living in FS endemic regions will be investigated. We will determine whether the IgE response is triggered by environmental antigen LJM11, which would then lead to autoantibody development. This will answer the critical question as to whether anti-Dsg1 IgE autoantibodies in FS susceptible individuals are originated from IgE response to environmental antigen. 3) In the third aim, we will identify those IgE clonal related IgG4 autoantibodies and determine the mechanism of their development. We will also investigate the pathogenicity of these IgG4 autoantibodies in vivo and in vitro to determine whether those IgE clonal related IgG4 autoantibodies participate in the pathogenesis in FS. The successful completion of this investigation will reveal the etiological mechanism of autoantibody development in genetically FS susceptible individuals. In addition, our studies of the mechanism of IgE antibody development before the onset of FS may substantiate that the presence of IgE antibodies is an early indication that an individual is at risk of developing FS, thus providing us with a valuable disease marker for FS and/or other IgG4-related diseases.
The endemic nature of fogo selvagem (FS) provides us an invaluable model to study the etiology mechanism of autoimmune skin diseases. This investigation aims at the understanding of the mechanism on how IgE response to environmental antigens in FS endemic regions leads to the development of FS.
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| 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 |
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| 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 |
