Transcriptome analysis of immune cells from Behçet’s syndrome patients: the importance of IL-17-producing cells and antigen-presenting cells in the pathogenesis of Behçet’s syndrome

Abstract

Background Behçet’s syndrome (BS) is an immune-mediated disease characterized by recurrent oral ulcers, genital ulcers, uveitis, and skin symptoms. HLA-B51, as well as other genetic polymorphisms, has been reported to be associated with BS; however, the pathogenesis of BS and its relationship to genetic risk factors still remain unclear. To address these points, we performed immunophenotyping and transcriptome analysis of immune cells from BS patients and healthy donors. Methods ImmuNexUT is a comprehensive database consisting of RNA sequencing data and eQTL database of immune cell subsets from patients with immune-mediated diseases and healthy donors, and flow cytometry data and transcriptome data from 23 BS patients and 28 healthy donors from the ImmuNexUT study were utilized for this study. Differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify genes associated with BS and clinical features of BS. eQTL database was used to assess the relationship between genetic risk factors of BS with those genes. Results The frequency of Th17 cells was increased in BS patients, and transcriptome analysis of Th17 cells suggested the activation of the NFκB pathway in Th17 cells of BS patients. Next, WGCNA was used to group genes into modules with similar expression patterns in each subset. Modules of antigen-presenting cells were associated with BS, and pathway analysis suggested the activation of antigen-presenting cells of BS patients. Further examination of genes in BS-associated modules indicated that the expression of YBX3, a member of a plasmacytoid dendritic cell (pDC) gene module associated with BS, is influenced by a BS risk polymorphism, rs2617170, in pDCs, suggesting that YBX3 may be a key molecule connecting genetic risk factors of BS with disease pathogenesis. Furthermore, pathway analysis of modules associated with HLA-B51 indicated that the association of IL-17-associated pathways in memory CD8+ T cells with HLA-B51; therefore, IL-17-producing CD8+ T cells, Tc17 cells, may play a critical role in BS. Conclusions Various cells including CD4+ T cells, CD8+ T cells, and antigen-presenting cells are important in the pathogenesis of BS. Tc17 cells and YBX3 may be potential therapeutic targets in BS.

Decoding Behcet’s Uveitis: an In-depth review of pathogenesis and therapeutic advances

“…Transcriptomic studies have revealed an active NF-κB pathway in peripheral Th17 cells. Additionally, analysis techniques such as WGCNA and pathway enrichment have highlighted the activation of APCs in BD [ 11 , 129 ]. The expression of IL-27, both at the mRNA and protein levels, is found to be reduced in the PBMCs and serum of active BD patients.…”

Upper gastrointestinal involvement of Behçet's disease in Japan: endoscopic findings and clinical features

“…1 The cause of BD has not been fully elucidated; however, there is a genetic predisposition associated with human leukocyte antigen (HLA) -B51 and various immune cells, and some exogenous and environmental factors are thought to be involved in its pathogenesis. 2,3 The prevalence of BD is relatively high in Mediterranean countries and East Asia, including Japan, and its estimated prevalence in Japan is reported as 13.5 out of 100 000 people. 1 Gastrointestinal (GI) findings, also known as intestinal BD, are important manifestations of BD.…”

“…Behçet's disease (BD) is a refractory systemic inflammatory disease characterized by a set of clinical manifestations, including recurrent oral and genital ulcers, uveitis, cutaneous lesions, and multisystem involvements 1 . The cause of BD has not been fully elucidated; however, there is a genetic predisposition associated with human leukocyte antigen (HLA) ‐B51 and various immune cells, and some exogenous and environmental factors are thought to be involved in its pathogenesis 2,3 . The prevalence of BD is relatively high in Mediterranean countries and East Asia, including Japan, and its estimated prevalence in Japan is reported as 13.5 out of 100 000 people 1 …”