Title: Endothelial Cell Inflammasomes in ANCA-Associated Vasculitis
Investigator: Dan Jane-Wit, MD, PhD
Co-investigator: Caodi Fang, MS
Institution: Yale University
Award: $25,000 for the first year; $25,000 for the second year
ANCA-associated vasculopathy (AAV) are inflammatory disorders that include Wegener’s granulomatosis, microscopic polyangitis, and Churg-Strauss disease. These conditions are characterized by chronic inflammation leading to blockages of blood vessels and diminished blood flow to vital organs like the kidney. How inflammation causes these blockages to form is unknown.
In this proposal, we will study how interactions between two immune mechanisms, complement and CD4+ T cells, lead to blockages in blood vessels in AAV. Complement are immune proteins that circulate in the blood. During AAV, complement proteins are activated and self-assemble to form membrane attack complexes (MAC). MAC are pore-like structures that insert into the cell membranes of endothelial cells (EC), the cells that line blood vessels. When this occurs, we found that MAC causes EC to release IL-1beta, a secreted protein that enhances the activation of CD4+ T cells. IL-1beta enhanced activation of CD4+ T cells that went on to release a factor called IFN-gamma that led to blood vessel blockages. Thus, MAC deposition on EC led to EC release of IL-1beta which then enhanced activation of CD4+ T cells that released IFN-gamma to cause blood vessel blockages in AAV.
Using human biospecimens to increase the likelihood that our findings will be relevant to patients, we will study how a protein structure called the inflammasome is activated by MAC on EC to allow IL-1beta secretion. We will then examine the significance of the inflammasome in human coronary arteries in a humanized mouse model, and we will further test the clinical relevance of the inflammasome by analyzing its expression in AAV patient tissues. Our studies will lead to novel insights into how AAV causes blood vessel blockages and may lead to new therapies to prevent this from occurring.