First Department of Propaedeutic and Internal Medicine, Joint Academic Rheumatology Program, 'Laiko' General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Rheumatology (Oxford). 2024 Nov 1;63(11):3184-3190. doi: 10.1093/rheumatology/keae397.
Pathogenesis of antiphospholipid syndrome (APS) remains poorly elucidated. We aimed to evaluate for the first time kidney transcriptome profiles in primary APS vs systemic lupus erythematosus (SLE) and control subjects.
We performed RNA sequencing on archival formalin-fixed paraffin-embedded kidney biopsies from APS (n = 4), SLE (n = 5) and control (n = 3) individuals, differential gene expression analysis (DGEA) and enrichment analysis using gene ontology (GO) and CORUM, KEGG and Reactome pathway databases.
Two-dimensional projection showed a distinct gene profile in primary APS vs control kidneys samples, but similar to SLE. DGEA in APS vs controls returned 276 upregulated and 217 downregulated genes, while the comparison between APS and SLE identified 75 upregulated and 111 downregulated genes. In 276 upregulated genes, enriched GO terms were (innate) immune response, inflammatory response, leucocyte and lymphocyte activation, cytokine production and T cell activation. CORUM and KEGG revealed complement-related genes (C3, C4A, C4B). Expression levels showed logFC values of 2.25 (P = 1.58e-05) for C3, 2.17 (P = 2.69e-06) for C4A and 2.135 (P = 3.7e-06) for C4B in APS vs controls, without differences between APS and SLE. Interferon (IFN) alpha/beta signalling was revealed by Reactome. Expression levels of nine IFN-regulated genes found upregulated in APS vs control kidneys (P-values ≤ 0.001 for all). Examining neutrophil-extracellular traps (NETs)-related gene expression, 13 of 15 upregulated NETs-related genes exhibited higher expression in APS vs controls but not vs SLE.
Complement, interferon and NETs-related genes are highly expressed in APS kidney tissues, similarly to SLE, pointing out the role of innate immunity in APS nephropathy pathogenesis and potential treatment targets.
抗磷脂综合征（APS）的发病机制仍未阐明。我们旨在首次评估原发性 APS 与系统性红斑狼疮（SLE）和对照受试者的肾脏转录组谱。
我们对 APS（n=4）、SLE（n=5）和对照（n=3）个体的存档福尔马林固定石蜡包埋肾活检进行了 RNA 测序，进行差异基因表达分析（DGEA）和基因本体论（GO）、CORUM、KEGG 和 Reactome 途径数据库的富集分析。
二维投影显示原发性 APS 与对照肾脏样本的基因谱明显不同，但与 SLE 相似。APS 与对照相比，DGEA 有 276 个上调基因和 217 个下调基因，而 APS 与 SLE 相比，有 75 个上调基因和 111 个下调基因。在 276 个上调基因中，富集的 GO 术语为（先天）免疫反应、炎症反应、白细胞和淋巴细胞激活、细胞因子产生和 T 细胞激活。CORUM 和 KEGG 揭示了补体相关基因（C3、C4A、C4B）。在 APS 与对照相比，C3 的表达水平为 2.25（P=1.58e-05），C4A 的表达水平为 2.17（P=2.69e-06），C4B 的表达水平为 2.135（P=3.7e-06），而 APS 与 SLE 之间没有差异。通过 Reactome 揭示了干扰素（IFN）α/β信号。在 APS 与对照肾脏中，有 9 个 IFN 调节基因上调（所有基因 P 值均≤0.001）。检查中性粒细胞胞外陷阱（NETs）相关基因表达时，在 APS 与对照相比，15 个 NETs 相关基因中有 13 个基因上调，但与 SLE 相比没有差异。
补体、干扰素和 NETs 相关基因在 APS 肾脏组织中高度表达，与 SLE 相似，这表明先天免疫在 APS 肾病发病机制中的作用和潜在的治疗靶点。
