Transcriptome Sequencing Reveals Potential Roles of ICOS in Primary Sjögren's Syndrome.

Jing Luo,Xin Xu,Lixia Zhu,Xiaobing Wang,Xin Liao,Senhong Ying,Suxian Lin,Mengjiao Yu,Lihe Zhang

doi:10.3389/fcell.2020.592490

Abstract

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by exocrine gland damage and extraglandular involvements. To identify potential biomarkers for the early detection of pSS and to further investigate the potential roles of the biomarkers in the progression of pSS, our previous RNA sequencing data and four microarray data of salivary glands (SGs) were combined for integrative transcriptome analysis between pSS and non-pSS. Differential gene expression analysis, gene co-expression network analysis, and pathway analysis were conducted to detect hub genes, which were subsequently investigated in peripheral blood mononuclear cell (PBMC) and plasma. Correlation analysis, single-gene Gene Set Enrichment Analysis, and receiver operating characteristic (ROC) curve were applied to investigate the potential function of the hub genes and their classification capacity for pSS. A total of 51 common up-regulated genes were identified among different pSS cohorts. A key module was found to be the most closely linked to pSS, which was significantly associated with inflammation-related pathways. Seven overlapped hub genes (ICOS, SELL, CR2, BANK1, MS4A1, ZC3H12D, and CCR7) were identified, among which ICOS was demonstrated to be involved in most crucial immune pathways. ICOS was up-regulated not only in SGs but also in PBMC and plasma in pSS, and the expression of ICOS was closely associated with lymphocytic infiltration in SGs and disease activity of pSS patients. It showed a strong classification capacity with classic clinical index in SGs (ROC curve 0.9821) and significant distinct discrimination in PBMC (ROC curve 0.9107). These findings are expected to gain a further insight into the pathogenesis of pSS and provide a promising candidate for the early detection of pSS.

Highlights

Primary Sjögren’s syndrome is a chronic systemic autoimmune disorder characterized by exocrine gland damage caused by focal lymphocytic infiltration especially presenting as xerostomia and xerophthalmia in nearly 90% patients (Seror et al, 2010; Manuel et al, 2017)
principal component analysis (PCA) analysis revealed that the Primary Sjögren’s syndrome (pSS) samples and the controls were generally separated into two distinct clusters (Supplementary Figures 1D,E), indicating the discriminative gene expression pattern of pSS
The PCA analysis revealed that the pSS and the non-pSS groups were clearly separated into two distinct clusters with obvious spatial separation (Supplementary Figure 1C)

Summary

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disorder characterized by exocrine gland damage caused by focal lymphocytic infiltration especially presenting as xerostomia and xerophthalmia in nearly 90% patients (Seror et al, 2010; Manuel et al, 2017). ICOS as Biomarkers of pSS women between 30 and 50 years (Ramos-Casals et al, 2015; Brito-Zeron et al, 2016). Besides the dysfunction of exocrine glands, extraglandular involvements are widely varied, ranging from mild non-specific symptoms including arthralgia, fatigue, and rash to severe systemic involvement, such as interstitial pneumonia, tubulointerstitial nephritis, neuropathy, and lymphoma, leading to poor prognosis and increased social burden (Ramos-Casals et al, 2012). The identification of biomarkers of pSS by high-throughput technologies may contribute to elucidating the molecular mechanism, improving on current classification criteria, and providing insight into any possible therapeutic targets (Aqrawi et al, 2017; Baldini et al, 2018). In vitro experiments demonstrated that interleukin 17 (IL-17)-producing helper T cells (Th17)like [CD4(+) CXCR5(+) CCR6(+)] T cells in circulation were found to be significantly higher in pSS than that in controls, and activated TH17-like cells could regulate follicular helper T cell (Tfh cell) differentiation and facilitate naïve B cells producing immunoglobulin (Li et al, 2012)

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