Meghan Free, PhD
Meghan Free, PhD
Meghan Free is a researcher at the University of North Carolina’s Kidney Center and UNC’s Division of Nephrology and Hypertension. She conducted her doctoral training with Dr. Ronald Falk in the Departments of Medicine and Pathology and Laboratory Medicine at UNC Chapel Hill. External funding support for Dr. Free’s research and training has been provided by the National Institutes of Health.
Research Summary
Our focus is to understand the cellular and molecular underpinnings of autoimmune kidney diseases, with a focus on anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. We are interested in the numerous aberrancies within T cells that are found in patients with ANCA vasculitis. Namely, we focus on detecting and deciphering the generation of autoreactive T cells, unraveling the dysfunctional nature of regulatory T cells, and new insights into cytotoxic CD4+ T cells. Our investigations utilize a range of techniques including flow cytometry, single cell and bulk RNA-sequencing, cell culture to assess cellular function and suppression, and ELISAs to detect secreted proteins. Collectively, we aim to develop biomarkers to predict both disease relapse and stable disease remission and work towards therapies to restore functionally suppressive regulatory T cells.
Regulatory T cells (Tregs) are a subset of T cells that are essential for regulation of the immune system. In many autoimmune diseases, including ANCA vasculitis, Tregs are not optimally functional. This could be due in part to changes in key subsets of Tregs and/or mechanistic changes that render Tregs unable to perform all of their suppressive functions. We have previously demonstrated that Tregs from ANCA vasculitis patients are unable to suppress effector T cell proliferation and cytokine production and that there are dynamic changes in Treg subsets that correlate with disease activity. Moreover, we investigated if transfer of functional Tregs in our mouse model of MPO-ANCA glomerulonephritis could ameliorate disease. Through single cell RNA-sequencing of Tregs from patients with ANCA vasculitis at various disease activities, we now have multiple lines of investigation to decipher key changes in Treg subsets and functional capacities. Our penultimate goal is to determine druggable pathways to therapeutically enhance Treg functions to induce long-lasting drug-free remission in ANCA vasculitis. UMAP of Treg subsets from scRNA-sequencing analyses. Related publications: Generation of immune cells that target “self” proteins (autoreactive cells) is an inevitable occurrence in the immune system. While the immune system contains a series of checks and balances to prevent escape of pathological autoreactive immune cells, this system can be faulty in some individuals and eventually lead to autoimmune disease. In ANCA vasculitis, we know the immune system targets one of two proteins: myeloperoxidase (MPO) or proteinase 3 (PR3). The autoantibodies in ANCA vasculitis targeting either MPO or PR3 are produced by B cells. Generation of class-switch, high-affinity ANCAs requires upstream help from T cells. Therefore, we have also focused on detecting and deciphering autoreactive T cells in the circulation of patients with ANCA vasculitis. We have utilized human leukocyte antigen (HLA) tetramers to detect and profile T cells that react to portions of either MPO or PR3. These studies have allowed us to determine key immunogenic regions of the autoantigens that may be inciting disease. Additionally, we know that these autoreactive T cells are clonally expanded as a result of chronic antigen stimulation and are capable of producing proinflammatory cytokines. Future studies are aimed to granularly track autoreactive T cells over the course of disease activity, determine their interactions with B cells and neutrophils, and generation of therapies to selectively target only autoreactive T cells. Highlighted portions of MPO that are targeted by the immune system (ANCAs, CD4+ and CD8+ T cells). Related publications:
