干燥综合征唾液腺的转录组分析确定了与类风湿因子和抗La/SSB血清阳性相关的滤泡和滤泡外反应相关的特征。

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.

作者信息

Pontarini Elena, Lucchesi Davide, Sciacca Elisabetta, Cavallaro Giulia, Song Qingxuan, Galbraith David, Thomas Elizabeth, Marino Annalisa, Sutcliffe Nurhan, Tappuni Anwar R, Giacomelli Roberto, Pulvirenti Alfredo, Bowman Simon J, Hao Ling-Yang, Sivils Kathy, Pitzalis Costantino, Lewis Myles J, Bombardieri Michele

机构信息

Department of Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK.

出版信息

Ann Rheum Dis. 2025 Aug 21. doi: 10.1016/j.ard.2025.07.021.

DOI:10.1016/j.ard.2025.07.021

PMID:40846589

Abstract

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.

摘要

目的

本研究旨在识别与疾病活动的外周和组织生物标志物以及淋巴瘤风险因素相关的唾液腺（SG）转录组特征，为干燥综合征（SjD）分层提供信息。

方法

对来自伦敦玛丽女王大学（QMUL）探索性队列（SjD [n = 55] 和非特异性慢性涎腺炎[干燥，n = 44]）的唇腺进行批量RNA测序，并对干燥综合征抗B细胞治疗试验（TRACTISS）验证队列（SjD，n = 29）进行分析，整合转录组、临床、血清学和组织学数据。

结果

无监督基因聚类证实干燥组和SjD组之间存在明显的转录组分离。差异表达最显著的基因要么是所有SjD患者与干燥患者共有的，要么是SjD腺体特有的，伴有具有异位淋巴结构（ELS）特征的淋巴细胞浸润。在SjD中，主成分分析确定了很大一部分变异性与类风湿因子（RF）血清阳性相关，超过了与SG-ELS和抗Ro/干燥综合征抗原A（SSA）血清阳性相关的变异性。来自RF、抗Ro/SSA和抗La/SSB阳性患者的具有ELS的SjD-SG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患者不同）的无ELS的SG通过视黄酸诱导基因-I（RIG-1）内源性RNA（包括病毒）传感途径和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2个独立队列（QMUL和TRACTISS）中，鉴定出的IFN基因与血清RF水平呈强正相关。