Nguyen Robert D, Nortey Jeremy, Gebreegziabher Elisabeth, Hinterwirth Armin, Zhong Lina, Chen Cindi, Doan Thuy, Lietman Thomas M, Gonzales John A
Francis I. Proctor Foundation (R.D.N., J.N., E.G., A.H., L.Z., C.C., T.D., T.M.L., J.A.G.), University of California, San Francisco, CA; Department of Ophthalmology (T.D., T.M.L., J.A.G.), University of California, San Francisco, CA; Department of Ophthalmology (J.N.), Northwestern University, Chicago, IL.
Eye Contact Lens. 2025 May 2;51(7):304-311. doi: 10.1097/ICL.0000000000001186.
To create a comprehensive multi-tissue molecular atlas of Sjögren's disease by using unbiased RNA sequencing to identify differentially expressed genes (DEGs) in peripheral blood and conjunctival transcriptomes, and to characterize the ocular surface and gut microbiome profiles in participants classified as Sjögren's versus non-Sjögren's disease.
This exploratory study used high-throughput RNA sequencing to analyze peripheral blood, conjunctival swabs, and rectal swabs from participants (11 classified as Sjögren's disease and four classified as non-Sjögren's) to identify DEGs and microbial profiles that could distinguish these groups.
Differential gene expression analysis revealed upregulated type I interferon ( IFI44L , OASL , USP18 ) and complement pathways ( SERPING1 ) in peripheral blood, alongside activation of several novel pathways in the conjunctiva including intracellular vesicle trafficking ( HIP1, GOLIM4, FIG4 ), immunometabolism ( CERS5, HPRT1, ULK2 ), and cytoskeletal remodeling ( MARK1, IQCB1) in Sjögren's disease. In addition, distinct gut microbiome compositions were observed in Sjögren's disease participants, characterized by an increased presence of Lactobacillus reuteri species.
Using unbiased RNA sequencing, we confirmed the role of type I interferon and complement pathways in the peripheral blood and identified novel molecular signatures in the conjunctiva of Sjögren's disease participants. These newly identified pathways-involved in intracellular vesicle trafficking, immunometabolism, and cytoskeletal remodeling-expand our understanding of disease mechanisms beyond traditional immune pathways. In addition, we found distinct gut microbial profiles in Sjögren's disease participants, although ocular surface microbiome showed no significant differences. Such findings may suggest possible new therapeutic targets and allow for Sjögren's disease patient stratification. However, validation in larger cohorts is needed to establish clinical significance and potential applications in Sjögren's disease.
通过使用无偏RNA测序来鉴定外周血和结膜转录组中的差异表达基因（DEG），创建一份全面的干燥综合征多组织分子图谱，并对被分类为干燥综合征与非干燥综合征的参与者的眼表和肠道微生物组特征进行表征。
这项探索性研究使用高通量RNA测序来分析参与者（11名被分类为干燥综合征，4名被分类为非干燥综合征）的外周血、结膜拭子和直肠拭子，以鉴定可区分这些组别的DEG和微生物特征。
差异基因表达分析显示，外周血中I型干扰素（IFI44L、OASL、USP18）和补体途径（SERPING1）上调，同时在干燥综合征患者的结膜中，包括细胞内囊泡运输（HIP1、GOLIM4、FIG4）、免疫代谢（CERS5、HPRT1、ULK2）和细胞骨架重塑（MARK1、IQCB1）在内的几种新途径被激活。此外，在干燥综合征参与者中观察到不同的肠道微生物组组成，其特征是罗伊氏乳杆菌种类的存在增加。
通过无偏RNA测序，我们证实了I型干扰素和补体途径在外周血中的作用，并在干燥综合征参与者的结膜中鉴定出了新的分子特征。这些新发现的途径——涉及细胞内囊泡运输、免疫代谢和细胞骨架重塑——扩展了我们对疾病机制的理解，超越了传统免疫途径。此外，我们发现干燥综合征参与者有不同的肠道微生物特征，尽管眼表微生物组没有显著差异。这些发现可能提示了新的潜在治疗靶点，并有助于干燥综合征患者的分层。然而，需要在更大的队列中进行验证，以确定其在干燥综合征中的临床意义和潜在应用。
