Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
RMD Open. 2022 Nov;8(2). doi: 10.1136/rmdopen-2022-002672.
Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.
Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjD); n=27 Ro/SSA positive (SjD) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log fold change ≥2 or ≤0.5; p<0.05) were used to predict lncRNA function. was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted deletion ( ) and in vitro stimulation assays.
Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, , in SjD (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. was upregulated in all SjD cases. RNA-seq and pathway analyses of cells implicated roles in cytotoxic function, differentiation and IFNγ induction. was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells.
influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.
干燥综合征（SjD）是一种以外分泌腺炎症性破坏为特征的自身免疫性疾病。自身抗体阳性的 Ro/SSA（SjD）患者表现出更严重的疾病。长非编码 RNA（lncRNA）是一类功能多样的非蛋白编码 RNA，其在自身免疫性疾病发病机制中的作用尚未得到很好的描述。
对干燥综合征病例（n=23 Ro/SSA 阴性（SjD）；n=27 Ro/SSA 阳性（SjD）和健康对照（HCs；n=27）进行全血 RNA 测序（RNA-seq）。差异表达（DE）转录本（log 倍变化≥2 或≤0.5；p<0.05）的生物信息学和通路分析用于预测 lncRNA 功能。通过 CRISPR 靶向敲除（ ）和体外刺激实验对 HSB-2 细胞进行 RNA-seq 分析来研究 。
全血 RNA-seq 显示自身抗体特异性转录谱，并相对于 HCs 发现 SjD 病例中 DE 转录本不成比例地下调。16 个 DE lncRNA 在 SjD 中与干扰素（IFN）调节基因 ， 表现出相关表达（r≥0.65 或≤-0.6）；在免疫细胞系中，四个反义 lncRNA 表现出 IFN 调节表达。在所有 SjD 病例中均上调。 细胞的 RNA-seq 和通路分析表明其在细胞毒性功能、分化和 IFNγ 诱导中起作用。IFNγ 在髓样细胞系中诱导 ，在原代人 T 细胞中受钙调神经磷酸酶/NFAT 通路和 T 细胞受体（TCR）信号调节。
影响许多免疫细胞基因和生长因子的表达，可被 IFNγ 诱导，并受钙调神经磷酸酶信号和 TCR 配体结合调节。改变的 表达可能影响 SjD 中失调的 T 细胞炎症途径。
