Role of Cytosolic DNA Sensor in Allergic Airway Inflammation
Abstract
Worldwide, allergic rhinitis affects between 10% and 30% of the population. The medical records of discharged and active duty Soldiers between March 1, 2004 and May 1, 2007 showed that about 10% of Soldiers deployed to the Persian Gulf had allergic rhinitis vs. about 5% of the U.S. homeland-stationed personnel, suggesting that deployment overseas may substantially increase allergies. The airway epithelial cells are the first line of defense against potent allergens. In preliminary studies shown in this proposal, we unexpectedly found that exposure of airway epithelial cells to allergenic extracts rapidly stimulates accumulation of DNA in the cytoplasm. We further found that this cytoplasmic DNA forms a stable complex with a number of cytoplasmic proteins including a DNA repair protein in allergic but not non-allergic mice and humans. However, to the best of our knowledge, there is no published information about formation of such a complex in sensitized mice or humans, or its role in allergic immune response. The central hypothesis of this proposal is that allergic mice and humans develop an multiprotein DNA-associated complex (which we named Allergosome) in the airway epithelium that efficiently stimulates allergic inflammation. The hypothesis of this concept will be tested in three aims. Aim 1 will elucidate the role of individual components in Allergosome formation. Aim 2 will examine formation of Allergosome in the allergic human subjects exposed to ragweed pollen in a pollen exposure chamber and during the natural ragweed pollen season. Aim 3 will examine the role of neutrophils in formation of Allergosome and allergic immune response in mice and identify the most effective inhibitors that inhibits formation of Allergosome in sensitized mice. In future studies, we plan to perform a clinical trial with the most effective inhibitor identified in Aim 3 of the present study. We will test that inhibitor in ragweed-allergic human subjects exposed to ragweed pollen in a pollen exposure chamber using knowledge from Aim 2 of the current study to design the future study. If the future human trials of that inhibitor are also successful, these studies may identify a novel inhibitor that will be able to prevent allergic diseases in 10%-30% of the world’s population, including active duty military personnel such as those who were deployed in the Persian Gulf.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810743
Entities
People
- Sanjiv Sur
Organizations
- Baylor College of Medicine
- United States Army