Table_13_The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus.xlsx

IntroductionAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).MethodsWe performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.ResultsWe report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.DiscussionWe conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.

抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAVs）呈现复杂表型，与高死亡率及多器官受累相关。本研究旨在阐述AAVs的转录组景观和分子表型，并与系统性红斑狼疮（SLE）进行比较。研究方法包括对30例AAVs患者（包括肉芽肿性多血管炎/GPA和微小多血管炎/MPA）进行全血mRNA测序，结合功能富集和网络分析以识别异常通路。在独立队列的18例AAVs患者中验证了关键基因和通路。共表达网络和层次聚类分析识别了分子表型。多层级转录组与SLE的重叠分析基于我们已发表的142例患者的数据。结果显示，“全血管炎”特征包含1,982个差异表达基因，富集于白细胞分化、细胞因子信号传导、I型和II型干扰素信号传导以及异常B-T细胞免疫。活跃疾病以与细胞周期检查点和代谢通路相关的特征为标志，而ANCA阳性患者表现出体液免疫转录特征。GPA和MPA的差异表达分析揭示了前者存在IFN-g通路（除I型干扰素外）以及后者存在与自噬和mRNA剪接相关的基因异常表达。无监督分子分类分析揭示了四种表型，其中中性粒细胞脱颗粒、异常代谢和B细胞反应作为潜在的机制驱动因素。SLE中的转录组扰动和分子异质性更为显著。AAVs的分子分析和数据驱动聚类揭示了独特的转录通路，这些通路可能被用于靶向治疗。讨论部分，我们得出结论，AAVs的转录组分析揭示了可针对治疗进行靶向的特定表型和分子通路。与SLE相比，AAVs的转录组更为同质化和碎片化程度较低，这可能解释了其对治疗的响应率更高的原因。