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.

中文翻译：

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儿童期发病的狼疮性肾炎的特征是肾基质和浸润免疫细胞之间的复杂相互作用


患有系统性红斑狼疮 （SLE） 的儿童患肾病的风险增加，称为儿童期发病的狼疮性肾炎 （cLN）。解离肾组织的单细胞转录组学加深了我们对 LN 发病机制的理解，但空间分辨率的丧失阻碍了对原位细胞相互作用的询问。利用空间转录组学的技术进步，我们从 8 名 cLN 患者和 4 名对照个体中生成了空间分辨的单细胞分辨率肾组织图谱。将注释细胞分配到 30 种参考细胞类型，包括主要肾脏亚群和浸润免疫细胞。空间分布分析表明，个体免疫谱系定位于 cLN 肾脏的特定区域，包括转运至发炎肾小球的髓系细胞和聚集在肾小管间质免疫热点内的 B 细胞。基因表达随组织位置的变化而变化，证明了空间数据的整合如何为 SLE 的免疫发病机制提供新的见解。免疫表型的改变伴随着常驻肾基质细胞基因表达的平行变化。然而，cLN 疾病活动的组织学评分与单个肾小球水平的肾小球细胞转录特征之间几乎没有相关性。最后，我们确定了空间相关基因表达的模块，预测了在炎症诱导和肾小管间质纤维化发展中的作用。单细胞空间转录组学有助于深入了解 cLN 的分子异质性，为更具针对性和个性化的治疗方法铺平道路。