null Research seeks to help children with chronic kidney disease
RI-MUHC study makes a breakthrough discovery into the role of the immune system in childhood idiopathic nephrotic syndrome
January 11, 2024
Published recently in Nature Communications, a study by researchers at the RI-MUHC presents a breakthrough discovery, identifying the previously unrecognized role of B cells in the development of childhood idiopathic nephrotic syndrome (INS). This disease can cause recurring and unexpected episodes of debilitating swelling due to the massive loss of circulating protein in urine. It affects children and a growing number of adults.
This large translational study at the interface of nephrology and immunology was co-led by Tomoko Takano, MD, PhD, a senior scientist in the Metabolic Disorders and Complications Program, and Ciriaco Piccirillo, PhD, a senior scientist and co-leader of the Infectious Diseases and Immunity in Global Health Program at the Research Institute of the McGill University Health Centre (RI-MUHC). Their research team studied blood samples from healthy children and from children with active INS.
“Young patients with INS can be effectively treated by drugs that target B cells,” says Dr. Takano, who is also a clinician in the Division of Nephrology at the McGill University Health Centre. “This treatment is new, but unfortunately imperfect. The patients can frequently relapse after viral infection. As well, the treatment is not specific — it impacts all B cells, including the beneficial ones that are needed to protect patients from infection. The pathogenic B cells impacting INS are not yet well characterized, and we need to learn more about them so we can seek ways to selectively inhibit their function in INS and in other diseases.”
The team first compared cells from the blood of children with active INS and from healthy children using single-cell RNA sequencing. They found that B cells in children with active INS were hyperactivated.
“Next, we found that a specific kind of B cells called extrafollicular memory B cells were more present in blood samples from children with active INS,” says Tho Al-Aubodah, a doctoral candidate supervised by professors Piccirillo and Takano. “The genes necessary for generating these extrafollicular B cells were also expressed to a greater extent in children with INS than in their healthy counterparts.”
In other recent studies, these same extrafollicular B cells were implicated in the development of autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis. Given the activity of these B cells in children with INS, the research suggests there may also be an autoimmune origin for INS.
“Extrafollicular B cells are normally triggered during acute infection, giving rise to antibody-secreting cells,” adds Prof. Piccirillo. “Our discovery provides an immunological framework for understanding the strong association between INS relapse and respiratory illnesses caused by RSV, influenza or even SARS-CoV-2. Specifically, our work proposes that viral infection may trigger autoreactive extrafollicular B cells that will then produce pathogenic antibodies, namely the autoantibodies that target the kidney cells involved in this disease.”
“While our work strongly suggests that the extrafollicular B cell response is implicated in INS, we still need direct evidence showing that these B cells do indeed produce pathogenic antibodies,” concludes Tho Al-Aubodah. “Our next steps include several promising avenues using both human materials and a novel mouse model for the disease.”
The authors gratefully acknowledge funding from the Canadian Institutes of Health Research, Kidney Foundation of Canada and MUHC Foundation.They also thank the Immunophenotyping Platform and the Centre of Excellence in Translational Immunology of the RI‑MUHC for their continued support.
The research team is part of the multicentre Canadian Childhood Nephrotic Syndrome Project that aims to better understand the causes and outcomes of INS to ultimately identify better therapeutics.
About the study
Read the publication: Al-Aubodah, TA., Aoudjit, L., Pascale, G. et al. The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome Nat Commun 14, 7682 (2023). https://doi.org/10.1038/s41467-023-43504-8