Ryan Flynn, MD, PhD
Boston Children’s Hospital
Harvard University
In collaboration with
Livia Casciola-Rosen
Antony Rosen
Johns Hopkins University School of Medicine
Project Overview
A characteristic feature of autoimmune rheumatic diseases, such as scleroderma, lupus, and Sjogren’s syndrome, is that distinct clinical subtypes and disease trajectories are associated with specific autoantibodies to targeted molecules. For example, autoantibodies to RNA polymerase-3 are strongly associated with diffuse scleroderma, a propensity to develop severe skin disease, and higher risk for scleroderma renal crisis.
Frequently, these targeted molecules (eg: RNA polymerase-3) bind nucleic acids, particularly RNA. From a mechanistic perspective, developing antibodies against these targeted molecules is strange, because they are usually hidden within the cell. How the immune system comes into contact with these targeted molecules, which is required in order to mount a specific response (autoantibodies) against them, remains unclear.
During his postdoctoral fellowship in the laboratory of 2022 Nobel Laureate, Carolyn Bertozzi, Dr. Flynn made a startling and groundbreaking discovery: that the surface of living cells is decorated with small RNAs that are modified with a specific type of sugar molecule (glycoRNAs). Interestingly, many of these small RNAs have been shown to be components of, or to interact with, the molecules commonly targeted in autoimmune rheumatic diseases.
Dr. Flynn has discovered that these small glycoRNAs occur in distinct patterns on different cells and in tissues, and that these patterns change when cells are stressed, injured, or altered by disease. Dr. Flynn is investigating whether disruption of normal, healthy patterns of cell-surface glycoRNAs may play a role in autoimmunity by potentially bringing novel molecules or parts of molecules to the cell surface where they can be detected and targeted by the immune system.
