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）患者的临床病程往往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（genome-wide DNA methylation, DNAm）谱分析已有开展，但目前尚无针对儿童起病SLE的对应研究数据。因此，本研究针对多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例中国儿童起病SLE患者及13例健康对照者的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）与全血样本的DNAm谱进行了比对分析。通过比对全血及各独立细胞谱系中的DNAm水平，本研究鉴定出21个覆盖15个基因的CpG位点存在一致性的DNAm缺失模式，构成了本研究队列中儿童起病SLE特异性且稳定的DNAm特征。此外，在新发基因及已被证实参与SLE发病机制的基因中，均观察到细胞谱系特异性的DNAm变化，包括甲基化缺失与获得。本研究同时强调，相较于仅分析全血样本，研究不同免疫细胞谱系的DNAm变化具有重要意义——细胞类型特异性的DNAm改变有助于阐明SLE的细胞类型特异性分子病理生理机制。