Mapping B cell pathways to podocyte reactivity across the spectrum of idiopathic podocytopathy
Co-applicant(s): Ciriaco Piccirillo, Susan Samuel
Lay Abstract
Background: Idiopathic podocytopathies are kidney diseases that damage specialized cells called podocytes, resulting in significant protein loss in the urine. These disorders include minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), which together form a spectrum ranging from mild, steroid-responsive illness in children to more severe, treatment-resistant forms in adults. While their precise causes remain unknown, increasing evidence indicates that these conditions may result from an autoimmune process in which the immune system mistakenly targets podocytes.
Our previous discoveries: Our research has shown that many patients with these diseases have autoantibodies - immune proteins that attack the body’s own tissues - directed against podocyte proteins such as Nephrin. These autoantibodies are more frequent and complex in adults, suggesting that the immune response evolves with age. In children, the immune system tends to produce these antibodies through a rapid, simplified pathway, whereas in adults, the response appears more mature, sustained, and diversified.
Objective: We aim to determine how the immune system produces these pathogenic autoantibodies and how this process differs between children and adults. Understanding these differences may explain why some patients respond well to treatment while others develop more severe, resistant disease.
Methods:
Aim 1: Identifying B Cells that target Nephrin We will study B cells that react to Nephrin at different stages of disease. Using advanced methods, we’ll determine if these B cells come from two main pathways: one typically seen in children that is more responsive to treatment, and another common in adults that may be less responsive. We will also analyze these cells in detail to understand the structure of the antibodies they produce and how these traits relate to the severity of the disease.
Aim 2: Exploring Antibody Features We will use a cutting-edge technique called LIBRA-seq, which helps us look at many features of B cells at once. This includes understanding how B cells may react to multiple targets (polyreactivity) and how the immune response can expand to new targets (epitope spreading). By studying these aspects, we aim to connect the characteristics of these B cells and their antibodies to how the disease progresses and how well treatments work.
Significance: By clarifying how the immune system contributes to podocyte injury, this research will deepen our understanding of the causes of nephrotic syndrome and help develop more precise, less toxic treatments. Ultimately, these insights could lead to safer and more effective therapies for both children and adults affected by idiopathic podocytopathies.
