Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis (AAV) is a systemic autoimmune disease caused by pathogenic autoantibodies. The disease causes inflammation of small blood vessels in the kidneys, respiratory tract, and other organs leading to irreversible organ damage. Current immunosuppressive treatment strategies are often complicated by infections, adverse metabolic effects, infertility, and the development of malignancies. AAV is marked by a relapsing course in many patients. Unfortunately, there are currently no tools available to reliably predict the risk of disease relapse or response to treatment in individual patients. This leads to large numbers of patients at low risk for disease relapse who are unnecessarily subjected to prolonged courses of toxic treatment regimens. Leukotrienes (LTs) are fatty acid mediators generated from arachidonic acid (AA) metabolism. The intracellular assembly of 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP) into the LT biosynthetic complex on the nuclear envelope, and their subsequent generation of LTB4, has been observed in activated neutrophils. Using fluorescence lifetime imaging microscopy (FLIM), we have generated preliminary data demonstrating an increase in 5-LO/FLAP interactions in the setting of active AAV. We now seek to extend these findings by determining if 5-LO/FLAP interactions can predict disease activity in a large cohort of patients with AAV.
In Aim 1, we investigate whether an increase in 5-LO/FLAP interactions precedes, and can therefore predict, clinical disease flare.
In Aim 2, we investigate whether treatment with immunosuppression in patients with active AAV leads to an attenuation in 5-LO/FLAP interactions. The knowledge gained may ultimately allow for tailoring of treatment regimens to disease activity on an individual basis.
Leukotrienes are bioactive lipid signaing molecules that play important roles in physiology and disease. This project will provide a new understanding of the pathogenesis of ANCA vasculitis by defining a class of lipid molecules and protein-protein interactions that have not been previously implicated with this disease. These findings will potentially lead to novel therapeutic targets in kidney disease.
