Elena Pontarini, Davide Lucchesi, Elisabetta Sciacca, Giulia Cavallaro, Qingxuan Song, David Galbraith, Elizabeth Thomas, Annalisa Marino, Nurhan Sutcliffe, Anwar R Tappuni, Roberto Giacomelli, Alfredo Pulvirenti, Simon J Bowman, Ling-Yang Hao, Kathy Sivils, Costantino Pitzalis, Myles J Lewis, Michele Bombardieri
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The most differentially expressed genes were either common to all SjD's versus sicca or specific to SjD's glands with lymphocytic infiltrates with features of ectopic lymphoid structures (ELS). In SjD, principal component analysis identified a significant proportion of variability associated with rheumatoid factor (RF)-seropositivity, exceeding that associated with SG-ELS and anti-Ro/Sjögren's syndrome antigen-A (SSA) seropositivity. Transcriptomes of SjD-SG with ELS from patients with positivity for either RF, anti-Ro/SSA, and anti-La/SSB showed mainly genes associated with germinal centre formation. Conversely, SG without ELS from patients with either RF or double anti-Ro (SSA)/anti-La (SSB) seropositivity (unlike patients with seronegative or single anti-Ro/SSA seropositivity) displayed a unique extrafollicular B-cell gene set associated with type-I interferon (IFN), through the retinoic acid-inducible gene-I (RIG-1) endogenous RNAs (including viral) sensing pathway and E3-ubiquitin ligases. The identified IFN genes showed strong positive correlations with serum RF levels in 2 independent cohorts (QMUL and TRACTISS).</p><p><strong>Conclusions: </strong>Comprehensive SG bulk-RNA sequencing provided the first transcriptomic evidence of distinct RF and anti-La/SSB-driven SG transcriptomic signatures in patients with SjD with and without ELS. These findings suggest that both classical follicular and extrafollicular viral-associated responses contribute to the selection of autoreactive B-cells in the glands of patients with SjD.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcriptomic profiling of Sjögren's disease salivary glands identifies signatures associated with both follicular and extrafollicular responses linked to rheumatoid factor and anti-La/SSB seropositivity.\",\"authors\":\"Elena Pontarini, Davide Lucchesi, Elisabetta Sciacca, Giulia Cavallaro, Qingxuan Song, David Galbraith, Elizabeth Thomas, Annalisa Marino, Nurhan Sutcliffe, Anwar R Tappuni, Roberto Giacomelli, Alfredo Pulvirenti, Simon J Bowman, Ling-Yang Hao, Kathy Sivils, Costantino Pitzalis, Myles J Lewis, Michele Bombardieri\",\"doi\":\"10.1016/j.ard.2025.07.021\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>This study aims to identify salivary gland (SG) transcriptomic signatures associated with peripheral and histological biomarkers of disease activity and lymphoma risk factors to inform on Sjögren's disease (SjD) stratification.</p><p><strong>Methods: </strong>Bulk RNA-sequencing of labial SG from exploratory Queen Mary University of London (QMUL) cohort (SjD [n = 55] and non specific-chronic-sialadenitis [sicca, n = 44]) and trial for anti-B-cell therapy in Sjogren's syndrome (TRACTISS)validation cohort (SjD, n = 29) analysed integrating transcriptomic, clinical, serological, and histological data.</p><p><strong>Results: </strong>Unsupervised gene clustering confirmed clear transcriptome segregation between sicca and SjD. The most differentially expressed genes were either common to all SjD's versus sicca or specific to SjD's glands with lymphocytic infiltrates with features of ectopic lymphoid structures (ELS). In SjD, principal component analysis identified a significant proportion of variability associated with rheumatoid factor (RF)-seropositivity, exceeding that associated with SG-ELS and anti-Ro/Sjögren's syndrome antigen-A (SSA) seropositivity. Transcriptomes of SjD-SG with ELS from patients with positivity for either RF, anti-Ro/SSA, and anti-La/SSB showed mainly genes associated with germinal centre formation. Conversely, SG without ELS from patients with either RF or double anti-Ro (SSA)/anti-La (SSB) seropositivity (unlike patients with seronegative or single anti-Ro/SSA seropositivity) displayed a unique extrafollicular B-cell gene set associated with type-I interferon (IFN), through the retinoic acid-inducible gene-I (RIG-1) endogenous RNAs (including viral) sensing pathway and E3-ubiquitin ligases. The identified IFN genes showed strong positive correlations with serum RF levels in 2 independent cohorts (QMUL and TRACTISS).</p><p><strong>Conclusions: </strong>Comprehensive SG bulk-RNA sequencing provided the first transcriptomic evidence of distinct RF and anti-La/SSB-driven SG transcriptomic signatures in patients with SjD with and without ELS. 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引用次数: 0
摘要
目的：本研究旨在鉴定唾液腺（SG）与疾病活跃性和淋巴瘤危险因素的外周和组织学生物标志物相关的转录组学特征，为Sjögren's疾病（SjD）分层提供信息。方法：对来自伦敦玛丽女王大学（Queen Mary University of London， QMUL）探索性队列（SjD [n = 55]和非特异性慢性涎腺炎[sicca， n = 44]）和干燥综合征（TRACTISS）抗b细胞治疗验证队列（SjD, n = 29）的唇部SG进行大量rna测序，整合转录组学、临床、血清学和组织学数据进行分析。结果：无监督基因聚类证实了sicca和SjD之间明显的转录组分离。差异表达最多的基因要么是所有SjD与sicca共同的，要么是具有异位淋巴结构（ELS）特征的淋巴细胞浸润的SjD腺体所特有的。在SjD中，主成分分析发现了与类风湿因子（RF）血清阳性相关的显著变异性比例，超过了与SG-ELS和抗ro /Sjögren s综合征抗原- a （SSA）血清阳性相关的变异性比例。来自RF、抗ro /SSA和抗la /SSB阳性患者的SjD-SG伴ELS的转录组主要显示与生发中心形成相关的基因。相反，来自RF或双抗ro (SSA)/抗la （SSB）血清阳性患者（与血清阴性或单抗ro /SSA血清阳性患者不同）的无ELS患者的SG通过视黄酸诱导基因i （RIG-1）内源性rna（包括病毒）感应途径和e3泛素连接酶，显示出与i型干扰素（IFN）相关的独特滤泡外b细胞基因集。在两个独立的队列（QMUL和TRACTISS）中，鉴定的IFN基因与血清RF水平呈强正相关。结论：全面的SG大体积rna测序提供了首个转录组学证据，证明在伴有和不伴有ELS的SjD患者中存在明显的RF和抗la / ssb驱动的SG转录组学特征。这些发现表明，经典的滤泡和滤泡外病毒相关反应都有助于SjD患者腺体中自身反应性b细胞的选择。
Transcriptomic profiling of Sjögren's disease salivary glands identifies signatures associated with both follicular and extrafollicular responses linked to rheumatoid factor and anti-La/SSB seropositivity.
Objectives: This study aims to identify salivary gland (SG) transcriptomic signatures associated with peripheral and histological biomarkers of disease activity and lymphoma risk factors to inform on Sjögren's disease (SjD) stratification.
Methods: Bulk RNA-sequencing of labial SG from exploratory Queen Mary University of London (QMUL) cohort (SjD [n = 55] and non specific-chronic-sialadenitis [sicca, n = 44]) and trial for anti-B-cell therapy in Sjogren's syndrome (TRACTISS)validation cohort (SjD, n = 29) analysed integrating transcriptomic, clinical, serological, and histological data.
Results: Unsupervised gene clustering confirmed clear transcriptome segregation between sicca and SjD. The most differentially expressed genes were either common to all SjD's versus sicca or specific to SjD's glands with lymphocytic infiltrates with features of ectopic lymphoid structures (ELS). In SjD, principal component analysis identified a significant proportion of variability associated with rheumatoid factor (RF)-seropositivity, exceeding that associated with SG-ELS and anti-Ro/Sjögren's syndrome antigen-A (SSA) seropositivity. Transcriptomes of SjD-SG with ELS from patients with positivity for either RF, anti-Ro/SSA, and anti-La/SSB showed mainly genes associated with germinal centre formation. Conversely, SG without ELS from patients with either RF or double anti-Ro (SSA)/anti-La (SSB) seropositivity (unlike patients with seronegative or single anti-Ro/SSA seropositivity) displayed a unique extrafollicular B-cell gene set associated with type-I interferon (IFN), through the retinoic acid-inducible gene-I (RIG-1) endogenous RNAs (including viral) sensing pathway and E3-ubiquitin ligases. The identified IFN genes showed strong positive correlations with serum RF levels in 2 independent cohorts (QMUL and TRACTISS).
Conclusions: Comprehensive SG bulk-RNA sequencing provided the first transcriptomic evidence of distinct RF and anti-La/SSB-driven SG transcriptomic signatures in patients with SjD with and without ELS. These findings suggest that both classical follicular and extrafollicular viral-associated responses contribute to the selection of autoreactive B-cells in the glands of patients with SjD.
期刊介绍：
Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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