T Cell Dysregulation in Patients with ANCA Disease
Dr. Ronald Falk, MD
Dr. Maureen Su, MD
Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a group of diseases which exhibit pauci-immune necrotizing crescentic glomerulonephritis and small vessel vasculitis. It is established that ANCA target either myeloperoxidase (MPO) or proteinase-3 (PR3); antigens found in the cytoplasm of neutrophils and monocytes. In vitro, ANCA bind surface expressed antigen and in combination with Fc receptor engagement, stimulate neutrophil degranulation. This inappropriate release of granule constituents results in injury to blood vessel endothelium, leading to inflammation and necrosis.
Patients with ANCA disease can be stratified based on their ANCA reactivity (MPO or PR3). Generally, patients have pathologically identical kidney disease and exhibit vasculitis. However, the long term disease course is strikingly different between the two patient cohorts. Patients serologically positive for MPO often achieve life-long remission, while patients positive for PR3 cycle between periods of relapsing active disease and remitting disease states. The basis for this disease course disparity is unknown, despite the fact that several other autoimmune diseases follow this cyclic disease course.
Several studies have established that patients with ANCA disease have CD4+ T cells in the periphery specific for MPO or PR3. The CD4+ T cell compartment is not homogenous and subsets of CD4+ T cells have varying roles from promoting inflammation to downregulating effector cells and dampening inflammation. Could the basis of relapsing and remitting disease stem from alterations in one or more subsets of the T cell compartment?
The focus of my project is to investigate immunological factors that explain remitting and relapsing episodes in patients with autoimmune disease, with an emphasis on ANCA disease. Specifically, I will investigate phenotypic and mechanistic changes of regulatory T cells (Tregs) associated with relapse and remission in ANCA disease. Additionally, I will explore the newly described phenomenon of Tregs converting into Th17-like cells known to subsequently migrate into disease affected tissues.