November 27, 2024 —

A study partly funded by the Lupus Research Alliance (LRA) and published in Science Translational Medicine used advanced technology to study where and how immune cells interact within kidney tissue in lupus nephritis (LN), a severe kidney disease caused by systemic lupus erythematosus (SLE). By applying a cutting-edge tool called spatial transcriptomics, Shaun Jackson, MD, Seattle Children’s Research Institute, and his team studied kidney biopsy samples from children with LN to uncover the disease’s underlying mechanisms and its heterogeneity (differences between patients). These unprecedented insights could pave the way for more targeted, personalized treatments. 

“This study revealed that certain immune cells target particular areas of the kidney during inflammation, leading to tissue damage,” noted Dr. Jackson. “This research challenges current methods of assessing disease severity and suggests why some treatments may work better for some patients than others, paving the way for doctors to better target therapies to individual children’s specific disease patterns.” 

Advanced Kidney Mapping of Immune Activity in Childhood Lupus Opens Door for Personalized Treatments 

Children with SLE face a higher risk of developing LN, which can cause lasting kidney damage over time. Because childhood-onset LN (cLN) begins at a young age, these patients experience more years of disease-related complications. This emphasizes the urgent need for treatments tailored to their unique disease features. However, children are often excluded from clinical trials, leaving many unanswered questions. 

With support from his LRA 2023 Lupus Mechanisms and Targets Award and 2023 Global Team Science Award, Dr. Jackson analyzed kidney tissue from eight children with cLN and four healthy children using the CosMx Spatial Molecular Profiler. This tool can examine over 900 genes and multiple immune cell types within specific areas of kidney tissue. Unlike previous studies that looked at dissociated (broken down) tissue, this approach preserves the tissue’s structure, offering a clearer picture of how immune cells and genes interact within different areas of the kidney.  

This analysis revealed several key insights into kidney inflammation in cLN, including:  

• The proportion of immune cells within the kidney tissue was elevated in children with cLN. Additionally, while tissue from healthy children showed limited interactions between immune cells, kidney samples from children with cLN revealed extensive interactions, forming “immune hotspots,” with B cells (a type of immune cell involved in lupus) at the center. 

• There was a surprising disconnect between the appearance of structures in the kidney and their gene signatures; even glomeruli (networks of tiny blood vessels in the kidney) that appeared normal under a microscope showed differences in gene expression in children with cLN. 

• The team identified multiple modules (distinct subsets) of genes in specific areas of the kidney including a module linked to fibrosis (scar tissue formation) that was elevated in children with cLN, highlighting a process that may contribute to long-term damage. 

 This study also sheds light on why some treatments, like rituximab, may not work for everyone. Rituximab targets B cells, but Dr. Jackson found that even after treatment, B cells persisted in the tissue of a child who didn’t respond to the therapy. This suggests that while the treatment removes B cells from the bloodstream, it may not fully deplete B cells from inflamed tissue, underscoring the need for therapies better equipped to target tissue-based B cells.  

Dr. Jackson’s study not only advances the understanding of childhood-onset lupus nephritis but also provides a valuable resource for other investigators studying lupus. By highlighting the unique biology of lupus in children, this work paves the way for more precise treatments designed to address their specific needs. 

“This work exemplifies how strategic research funding can drive medical breakthroughs that directly impact patient care, bringing hope to families affected by childhood lupus,” noted Dr. Jackson.