Expression and regulatory characteristics of peripheral blood immune cells in primary Sjögren’s syndrome patients using single-cell transcriptomic

Liu, Jinkun; Gao, Hongyan; Li, Chengyin; Zhu, Fenglin; Wang, Miao; Xu, Yan; Wu, Bin

doi:10.1016/j.isci.2022.105509

Cited by 21 publications

(15 citation statements)

References 42 publications

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“…This finding is consistent with greater type I and II IFN signatures reported in patients with SjD 71,72 and the Th1/IFN-γ dominated inflammation in SGs of Stim1/2 Foxp3 mice. Several CD4 + T cell subsets, including Th1, Tfh and naïve Treg cells, showed a depletion of ribosome-related pathways, which was also observed in other scRNA-seq studies of patients with SjD 73 . This is of note as auto-antibodies in SjD are directed against Ro and La ribonucleoproteins that are associated with the quality control of 5S ribosomal RNA 74 and maturation of RNA polymerase III 75 , potentially explaining the dysregulation of ribosomal related pathways in some CD4 + T cell subsets.…”

Section: Greater Ifn Signaling and Activity Of Th1 Cells Occurs In Pa...supporting

confidence: 79%

“…Similar transcriptomic analyses of Treg cells in SjD are not yet available. One scRNA-seq-based study investigating 3 patients with SjD and 3 controls concluded that there are no changes in Treg frequencies in patients 73 , whereas another scRNA-seq study of 5 patients and controls did not mention Treg cells 66 . Here, we report that the numbers of Foxp3 + naive and memory Treg cells are comparable in 9 patients with SjD and 8 relevant controls.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Wang,

Li,

McDermott

et al. 2024

Preprint

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Objectives. Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods. Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells fromStim1/2Foxp3mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results.Stim1/2Foxp3mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation inStim1/2Foxp3mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells fromStim1/2Foxp3mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4+T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions. We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.

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Section: Greater Ifn Signaling and Activity Of Th1 Cells Occurs In Pa...supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Wang,

Li,

McDermott

et al. 2024

Preprint

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“…Previous studies using scRNA-seq and analyzing PBMCs in a handful of patients with pSS have primarily reported differences in the T cell compartment, whereas the B cells were only briefly considered. 13,[24][25][26] Here, we assigned the individual B cells into 16 cellular states, all present in both patients and controls, but with a shift in the composition of B cell subtypes. The largest difference compared with controls was seen in the SSA/SSB+ patient group.…”

Section: Discussionmentioning

confidence: 99%

“…This is the first large‐scale study in which B cell composition and BCR gene usage have been investigated at the single‐cell level in patients with pSS stratified for SSA/SSB antibodies. Previous studies using scRNA‐seq and analyzing PBMCs in a handful of patients with pSS have primarily reported differences in the T cell compartment, whereas the B cells were only briefly considered 13,24–26 . Here, we assigned the individual B cells into 16 cellular states, all present in both patients and controls, but with a shift in the composition of B cell subtypes.…”

Section: Discussionmentioning

confidence: 99%

Multimodal Single‐Cell Sequencing of B Cells in Primary Sjögren's Syndrome

Arvidsson,

Czarnewski,

Johansson

et al. 2023

Arthritis & Rheumatology

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ObjectiveB cells are important in the pathogenesis of primary Sjögren's syndrome (pSS). Patients positive for SSA/SSB autoantibodies are more prone to systemic disease manifestations and adverse outcomes. We aimed to determine the role of B cell composition, gene expression and B cell receptor (BCR) usage in pSS subgroups stratified for SSA/SSB antibodies.MethodsOver 230 000 B cells were isolated from peripheral blood of pSS patients (n = 6 SSA‐, n = 8 SSA+ single positive and n = 10 SSA/SSB+ double positive) and four healthy controls, and processed for single cell RNA and VDJ sequencing.ResultsWe show that SSA/SSB+ patients present the highest and lowest proportion of naïve and memory B cells respectively, and the highest upregulation of interferon‐induced genes across all B cell subtypes. Differential usage of IGHV showed that IGHV1‐69 and IGHV4‐30‐4 were more often used in all pSS subgroups compared with controls. Memory B cells from SSA/SSB+ patients displayed a higher proportion of cells with unmutated VDJ transcripts compared to other pSS patient groups and controls, indicating altered somatic hypermutation processes. Comparison with previous studies revealed heterogeneous clonotype pools, with little overlap in CDR3 sequences. Joint analysis using scRNA‐seq and scVDJ‐seq data allowed unsupervised stratification pSS patients, and identified novel parameters that correlated to disease manifestations and antibody status.ConclusionWe describe heterogeneity and molecular characteristics in B cells from pSS patients, providing clues to intrinsic differences in B cells that affect the phenotype and outcome, allowing stratification of pSS patients at improved resolution.This article is protected by copyright. All rights reserved.

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“…In this concluding section, it is pertinent to showcase genes that exhibit coherent and cell-type-specific correlations between their expression and motif For instance, the transcription factor CEBPD, depicted in Fig. 7, is recognized for its role in the inflammatory response of monocytes [36][37][38]. This functional role is reflected in its expression and motif information, as illustrated in Fig.…”

Section: Tfs Characterize Cell Types At Both Expression and Motif Inf...mentioning

confidence: 99%

Cross-omic Transcription Factors meta-analysis: an insight on TFs accessibility and expression correlation

Martini,

Bardini,

Savino

et al. 2024

Preprint

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It is well-known how sequencing technologies propelled cellular biology research in recent years, giving an incredible insight into the basic mechanisms of cells. Single-cell RNA sequencing is at the front in this field, with Single-cell ATAC sequencing supporting it and becoming more popular. In this regard, multi-modal technologies play a crucial role, allowing the possibility to perform the mentioned sequencing modalities simultaneously on the same cells. Yet, there still needs to be a clear and dedicated way to analyze this multi-modal data. One of the current methods is to calculate the GAM, which summarizes the accessibility of the genes at the genomic level, to have a more direct link with the transcriptomic data. However, this concept is not well-defined, and it is unclear how various accessible regions impact the expression of the genes. Moreover, the transcription process is highly regulated by the Transcription Factors that binds to the different DNA regions. Therefore, this work presents a continuation of the meta-analysis of GAGAM contributions, aiming to investigate the correlation between the TFs expression and motif information in the different functional genomic regions to understand the different TF dynamics involved in different cell types.

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Expression and regulatory characteristics of peripheral blood immune cells in primary Sjögren’s syndrome patients using single-cell transcriptomic

Cited by 21 publications

References 42 publications

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Multimodal Single‐Cell Sequencing of B Cells in Primary Sjögren's Syndrome

Cross-omic Transcription Factors meta-analysis: an insight on TFs accessibility and expression correlation

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