Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells

• Published in: Science translational medicine 2024-11, Vol.16 (775), p.eadl1666
• Main Authors: Danaher, Patrick, Hasle, Nicholas, Nguyen, Elizabeth D, Roberts, Jordan E, Rosenwasser, Natalie, Rickert, Christian, Hsieh, Elena W Y, Hayward, Kristen, Okamura, Daryl M, Alpers, Charles E, Reed, Robyn C, Baxter, Sarah K, Jackson, Shaun W
• Format: Article
• Language: English
• Subjects: Adolescent; Age of Onset; Child; Children; Female; Fibrosis; Gene expression; Gene Expression Profiling; Glomerulus; Humans; Immunopathogenesis; Inflammation; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidneys; Lupus; Lupus nephritis; Lupus Nephritis - immunology; Lupus Nephritis - pathology; Lymphocytes B; Male; Myeloid cells; Phenotypes; Single-Cell Analysis; Spatial discrimination; Spatial distribution; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; Systemic lupus erythematosus; Transcriptome - genetics; Transcriptomics
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.adl1666

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.