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Immune cell and TCR/BCR repertoire profiling in systemic lupus erythematosus patients by single-cell sequencing.

ABSTRACT: The immune cells and the repertoire of T cells and B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Exploring their expression and distribution in SLE can help us better understand this lethal autoimmune disease. In this study, we used a single-cell 5' RNA sequence and single-cell T cell receptor (TCR)/B cell receptor (BCR) to study the immune cells and the repertoire from ten SLE patients and the paired normal controls (NC). The results showed that 9732 cells correspondence to 12 cluster immune cell types were identified in NC, whereas 11042 cells correspondence to 16 cluster immune cell types were identified in SLE. The results demonstrated that neutrophil, macrophage, and dendritic cells were accumulated in SLE by annotating the immune cell types. Besides, the bioinformatics analysis of differentially expressed genes (DEGs) in these cell types indicates their role in inflammation response. In addition, patients with SLE showed increased TCR and BCR clonotypes compared with the healthy controls. Furthermore, patients with SLE showed biased usage of TCR and BCR V(D)J genes. Taken together, we characterized the transcriptome and TCR/BCR immune repertoire profiles of SLE patients, which may provide a new avenue for the diagnosis and treatment of SLE.

SUBMITTER: Zheng F

PROVIDER: S-EPMC8610142 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo investigate the immune cell profiles of patients with systemic lupus erythematosus (SLE), and to identify longitudinal changes in those profiles over time.MethodsWe employed mass cytometry with 3 different panels of 38-39 markers (an immunophenotyping panel, a T cell/monocyte panel, and a B cell panel) in cryopreserved peripheral blood mononuclear cells (PBMCs) from 9 patients with early SLE, 15 patients with established SLE, and 14 controls without autoimmune disease. We used machine learning-driven clustering, flow self-organizing maps, and dimensional reduction with t-distributed stochastic neighbor embedding to identify unique cell populations in early SLE and established SLE. We used mass cytometry data of PBMCs from 19 patients with early rheumatoid arthritis (RA) and 23 controls to compare levels of specific cell populations in early RA and SLE. For the 9 patients with early SLE, longitudinal mass cytometry analysis was applied to PBMCs at enrollment, 6 months after enrollment, and 1 year after enrollment. Serum samples were also assayed for 65 cytokines using Luminex multiplex assay, and associations between cell types and cytokines/chemokines were assessed.ResultsLevels of peripheral helper T cells, follicular helper T (Tfh) cells, and several Ki-67+ proliferating subsets (ICOS+Ki-67+ CD8 T cells, Ki-67+ regulatory T cells, CD19intermediate Ki-67high plasmablasts, and PU.1high Ki-67high monocytes) were increased in patients with early SLE, with more prominent alterations than were seen in patients with early RA. Longitudinal mass cytometry and multiplex serum cytokine assays of samples from patients with early SLE revealed that levels of Tfh cells and CXCL10 had decreased 1 year after enrollment. Levels of CXCL13 were positively correlated with levels of several of the expanded cell populations in early SLE.ConclusionTwo major helper T cell subsets and unique Ki-67+ proliferating immune cell subsets were expanded in patients in the early phase of SLE, and the immunologic features characteristic of early SLE evolved over time.

Project description:BackgroundB lymphocytes (B cells) are essential in humoral response, and their activation is an important first step for the production of antibodies. However, aberrant B-cell activation is common in the development and progression of autoimmune diseases including systemic lupus erythematosus (SLE), which is characterized by the generation of superfluous autoantibodies. SLE exhibits clinical manifestation such as excessive inflammation and tissue damage. This review aims to summarize the recent emerging studies on aberrant B-cell activation and the associated concurrent therapeutic targets in SLE.SummaryAberrant B-cell activation is closely associated with the pathogenesis of SLE. Among a variety of mechanisms, dysregulations of B-cell receptor (BCR), toll-like receptor (TLR), and B-cell activating factor receptor (BAFF-R) pathways are the common and dominating factors involved in aberrant B-cell activation. These aberrant signaling transductions play diverse and integrated roles in the development and the pathogenesis of SLE. Therapies targeting aberrant B-cell activation have shown promising efficacy in achieving the clinical alleviation of SLE, suggesting the discovery of new drug targets from these aberrant signaling pathways is imminent. Here, an integrated survey or review of published high-throughput sequencing database covering RNAs of B cells from SLE versus criteria-matched healthy controls highlights that reported signaling molecules in BCR pathway (VAV2, PLC-γ2), TLR pathway (TLR9, P105, IRF7, TAB1), and BAFF-R pathway (SDF-1α) are attitudinally upregulated in SLE patients. This review thus suggests the concurrent and future therapeutic targets and potential biomarkers in both basic and clinical studies of SLE.Key messagesThis review focuses on core B-cell signaling pathways, discussing the progress in the role of aberrant B-cell activation during the pathogenesis of SLE. This review also highlights the signaling molecules from published studies and database for the possible prevention and treatment targets serving the future clinical treatments of SLE.

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Immune cell and TCR/BCR repertoire profiling in systemic lupus erythematosus patients by single-cell sequencing.

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