Cell Lineage-specific Genome-wide DNA Methylation Analysis of Patients with Paediatric-onset Systemic Lupus Erythematosus

Patients with paediatric-onset systemic lupus erythematosus (SLE) often present with more severe clinical courses than adult-onset patients. Although genome-wide DNA methylation (DNAm) profiling has been performed in adult-onset SLE patients, parallel data on paediatric-onset SLE are not available. Therefore, we undertook a genome-wide DNAm study in paediatric-onset SLE patients across multiple blood cell lineages. The DNAm profiles of four purified immune cell lineages (CD4+ T cells, CD8+ T cells, B cells and neutrophils) and whole blood were compared in 16 Chinese patients with paediatric-onset SLE and 13 healthy controls using the Illumina HumanMethylationEPIC BeadChip. Comparison of DNAm in whole blood and within each independent cell lineage identified a consistent pattern of loss of DNAm at 21 CpG sites overlapping 15 genes, which represented a robust, disease-specific DNAm signature for paediatric-onset SLE in our cohort. In addition, cell lineage-specific changes, involving both loss and gain of DNAm, were observed in both novel genes and genes with well-described roles in SLE pathogenesis. This study also highlights the importance of studying DNAm changes in different immune cell lineages rather than only whole blood, since cell type-specific DNAm changes facilitated the elucidation of the cell type-specific molecular pathophysiology of SLE.

儿童起病系统性红斑狼疮（paediatric-onset systemic lupus erythematosus, SLE）患者的临床病程通常较成人起病患者更为严重。尽管针对成人起病SLE患者的全基因组DNA甲基化（DNA methylation, DNAm）谱分析已见报道，但儿童起病SLE的同类数据仍较为匮乏。为此，本研究针对多类血细胞谱系的儿童起病SLE患者开展了全基因组DNA甲基化研究。本研究采用Illumina HumanMethylationEPIC BeadChip芯片，对16名中国儿童起病SLE患者与13名健康对照的4种纯化免疫细胞谱系（CD4+ T细胞、CD8+ T细胞、B细胞及中性粒细胞）及全血的DNA甲基化谱进行了对比分析。通过比较全血及各独立细胞谱系中的DNA甲基化水平，本研究在21个CpG位点（覆盖15个基因）中发现了一致的DNA甲基化丢失模式，该模式可作为本研究队列中儿童起病SLE的稳定疾病特异性DNA甲基化特征。此外，在新发基因及既往已被证实参与SLE发病机制的基因中，均观察到了细胞谱系特异性的DNA甲基化变化（包括甲基化缺失与获得）。本研究同时强调，不应仅依赖全血样本开展DNA甲基化变化研究，而应针对不同免疫细胞谱系展开分析——细胞类型特异性的DNA甲基化变化有助于阐明SLE的细胞类型特异性分子病理生理机制。