Andrea Fava, MD
2021 Recipient, Gary S. Gilkeson Career Development Award
Johns Hopkins University School of Medicine
Title of Project: Defining the role of immature neutrophil populations and IL-16 in lupus nephritis: a spatially resolved multiomics approach
Mentor: Michelle Petri, MD MPH
About the Researcher
Andrea Fava, MD, developed his passion for science and autoimmune diseases while in medical school at San Raffaele University in Milan (ranked as the #1 Medical School in Italy). As part of his research, he joined Anthony Fauci’s group at the NIH as a visiting student. He graduated Summa Cum Laude with a thesis on the role of viral infections in autoimmunity.
He then crossed the pond for a research fellowship at Johns Hopkins to study the mechanisms of the autoimmune disease scleroderma. His work focused on the identification and characterization of autoreactive immune cells that are thought to cause autoimmune manifestations such as skin or lung disease. His efforts led to the development of an assay to study autoreactive cells across multiple autoimmune diseases. Along with his team, he was able to demonstrate how an aberrant immune response to cancer may derange into autoimmunity in scleroderma. These breakthrough findings were ultimately published in the prestigious journal, Science.
After completing his residency at Johns Hopkins with several honors, such as the election as member of the Alpha Omega Alpha medical honor society and the Patrick Murphy Award for teaching excellence, Dr. Fava remained at Hopkins to pursue his clinical training in rheumatology. Further, he obtained additional training to learn how to care for patients with lupus and how to advance their treatment through research with a Lupus Fellowship mentored by Dr. Michelle Petri. He pursued training in computational biology and genomics in order to directly work with “big data.” To do so, he joined Soumya Raychaudhuri’s lab at the Broad Institute/Harvard as a visiting fellow in 2019. He became a member of the Accelerating Medicines Partnership (AMP), the NIH-led moon-shot project to understand the mechanisms of lupus nephritis. As part of AMP, he took the leadership in the analysis of urine proteomics data with the goal of developing a “liquid biopsy” that could allow the use of a urine test in place of a kidney biopsy to diagnose and treat lupus nephritis. He has also identified key biological differences in the mechanisms of lupus nephritis that may explain why African American patients suffer worse disease. His findings were selected for podium presentations (including a plenary session) at the American College of Rheumatology meetings in 2018, 2019, and 2020. His preliminary work on the urine proteomics was awarded the Lupus 2019 Scientific Merit Award at the International Congress on SLE in San Francisco. He has authored 16 publications, 7 of which as first author, and more are currently under review or in press.
Dr. Fava is now fully committed to become a physician-scientist focused on lupus. He has joined the faculty at Johns Hopkins at the rank of Instructor in January 2021. He is a faculty member in the Hopkins Lupus Center where he visits patients with SLE one day a week. The remainder of his effort is fully dedicated to lupus research.
Despite optimal treatment, up to 60% of patients with lupus nephritis develop irreversible kidney damage that ultimately leads to dialysis, renal transplantation, or death. The discovery of new mechanisms of kidney inflammation and damage is critical to develop better treatments.
We recently discovered that patients with the worst type of lupus nephritis (class 3 and 4) have high levels of IL-16 in the kidneys. IL-16 is a compound that immune cells make to attract and activate other immune cells to cause inflammation. We found that out of 1,200 compounds that we measured in the urine, IL-16 showed the strongest association with the amount of kidney inflammation suggesting a possible critical role in lupus nephritis.
The second group of compounds associated with lupus nephritis were “neutrophil granules”. Neutrophils are the most abundant immune cell type in the body. During inflammation, they release “granules” filled with inflammatory compounds aimed to kill microbes. However, in autoimmune diseases such as lupus nephritis, these inflammatory compounds may be inappropriately released and cause permanent kidney damage.
We think that IL-16 attracts a special type of “immature” neutrophil to the kidneys that can cause inflammation and irreversible damage in lupus nephritis.
Here, we want to better understand this process by 1) defining what makes IL-16 in the kidneys and 2) what this special type of neutrophil is doing in lupus nephritis. First, we will take stored kidney biopsies from lupus nephritis patients, and we will define the identity of IL-16-making cells using multicolor staining. For the second task, using a newly developed cutting-edge technology called “spatial transcriptomics”, we will measure all the active genes in the immature neutrophils in the kidney biopsies of lupus nephritis patients, thereby discovering their function.
This very exciting work will generate the knowledge base to devise new understandings and treatment strategies to prevent kidney inflammation and scarring, thereby saving kidneys and improving the quality of life of patients with lupus kidney disease.