Chen Jiaxu, Shi Zhenghao, Xue Luan
Department of Rheumatology and Immunology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200080, China.
Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Genes Genomics. 2025 May;47(5):559-569. doi: 10.1007/s13258-025-01633-y. Epub 2025 Mar 18.
Sjögren's syndrome (SS) is an autoimmune disorder affecting exocrine glands, causing dry mouth and eyes, with no effective treatment. While high-throughput sequencing has provided insights into its mechanisms, the role of alternative splicing (AS) in SS remains underexplored.
To investigate the relationship between immune infiltration in the salivary glands and AS events at the transcriptomic level, and to identify potential biomarkers that may be linked to the diagnosis and prognosis of SS.
Transcriptomic data from salivary glands were aligned to the GRCh38 genome using HISAT2. Isoform quantification was performed with StringTie, and differential isoform usage was analyzed with DEXSeq in the IsoformSwitchAnalyzeR pipeline. Further analyses were conducted to explore the relationship between AS events, clinical data and immune infiltration.
16 genes showed significant alternative splicing between biopsy-positive and biopsy-negative salivary glands. These genes were linked to immune regulation. Isoform usage ratios integrated with clinical data identified MAP4K1, SH2D3C, and ACAP1 isoforms as potential diagnostic biomarkers. Immune infiltration analysis showed a strong correlation between memory B cells, follicular helper T cells, and biopsy scores, with significant differences between biopsy-positive and biopsy-negative tissues. A correlation between immune infiltration and isoform usage provided insights into gene function and disease progression.
This study reveals the critical role of AS in SS, identifying 16 genes with differential isoform usage that may serve as biomarkers for diagnosis and prognosis. The link between immune infiltration and splicing suggests that AS influences immune responses in SS, providing opportunities for targeted therapies. These findings emphasize AS's importance in SS and offer new diagnostic and therapeutic avenues.
干燥综合征（SS）是一种自身免疫性疾病，影响外分泌腺，导致口干和眼干，目前尚无有效治疗方法。虽然高通量测序为其发病机制提供了一些见解，但可变剪接（AS）在干燥综合征中的作用仍未得到充分研究。
在转录组水平上研究唾液腺免疫浸润与可变剪接事件之间的关系，并确定可能与干燥综合征的诊断和预后相关的潜在生物标志物。
使用HISAT2将唾液腺的转录组数据与GRCh38基因组进行比对。用StringTie进行异构体定量，并在IsoformSwitchAnalyzeR管道中用DEXSeq分析差异异构体使用情况。进一步分析以探讨可变剪接事件、临床数据和免疫浸润之间的关系。
16个基因在活检阳性和活检阴性的唾液腺之间表现出显著的可变剪接。这些基因与免疫调节有关。结合临床数据的异构体使用比率确定MAP4K1、SH2D3C和ACAP1异构体为潜在的诊断生物标志物。免疫浸润分析显示记忆B细胞、滤泡辅助性T细胞与活检评分之间有很强的相关性，活检阳性和活检阴性组织之间存在显著差异。免疫浸润与异构体使用之间的相关性为基因功能和疾病进展提供了见解。
本研究揭示了可变剪接在干燥综合征中的关键作用，鉴定出16个具有差异异构体使用的基因，这些基因可能作为诊断和预后的生物标志物。免疫浸润与剪接之间的联系表明可变剪接影响干燥综合征中的免疫反应，为靶向治疗提供了机会。这些发现强调了可变剪接在干燥综合征中的重要性，并提供了新的诊断和治疗途径。
