Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Ann Rheum Dis. 2024 Sep 30;83(10):1322-1334. doi: 10.1136/ard-2023-225349.
Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE.
Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE.
ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles.
ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.
从先前的抗核抗体（ANA）阳性到系统性红斑狼疮（SLE）的临床演变的潜在机制尚未完全阐明。本研究旨在了解与亚临床 ANA 阳性、进展或不进展为 SLE 相关的血液免疫细胞转录特征。
对 35 名 ANA 阳性（ANA+）且有非诊断症状的受试者在基线时分离的外周血单个核细胞进行了批量 RNA 测序，采用差异基因表达、加权基因共表达网络分析、细胞亚群去卷积和功能富集分析进行分析。ANA+受试者，包括在 12 个月内进展为可分类 SLE 的受试者（n=15）和具有稳定亚临床 ANA 阳性的受试者（n=20），与 15 名健康受试者和 18 名 SLE 患者进行了比较。
与健康对照组相比，ANA+受试者表现出广泛的转录组失调，表现为 CD4+幼稚 T 细胞和静止 NK 细胞减少，但激活的树突状细胞增加。SLE 患者可见 B 细胞淋巴细胞减少，但 ANA+患者未见此现象。三分之二的失调基因在 ANA+进展者和非进展者中是共同的。ANA+进展者表现出上调的模块化干扰素特征，其中组成基因在体外均可被 I 型干扰素（IFN-I）和 II 型干扰素（IFN-II）诱导。基线下调线粒体氧化磷酸化复合物 I 成分与 SLE 进展显著相关，但与 IFN 模块化活性无直接相关性。非进展者表现出更多样的细胞因子谱。
无论临床轨迹如何，ANA 阳性均表现出明显的失调，在转录组上更接近 SLE，而不是健康的免疫功能。代谢紊乱和 IFN-I 激活发生在 ANA+临床前阶段早期，并与随后的临床演变区分开来的转录谱相关。
