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Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

ABSTRACT: The treatment of rheumatoid arthritis was revolutionized with the use of molecular-targeted drugs that target immunoregulatory molecules. The success of treatment with these drugs prompted the development of molecular-targeted drugs for systemic lupus erythematosus. However, systemic lupus erythematosus is a disease with high heterogeneous immune abnormalities, and diverse cells or molecules can be treatment targets. Thus, the identification of subpopulations based on immune abnormalities is essential for the development of effective treatment. One analytical method used to identify subpopulations is the immunophenotyping of peripheral blood samples of patients. This analysis evaluates the validity of target molecules for peripheral blood immune cell subsets, which are expected to be developed as biomarkers for precision medicine in which appropriate treatment targets are set for each subpopulation.

SUBMITTER: Nakayamada S

PROVIDER: S-EPMC10295858 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

Nakayamada Shingo S Tanaka Yoshiya Y

Biomolecules 20230608 6

The treatment of rheumatoid arthritis was revolutionized with the use of molecular-targeted drugs that target immunoregulatory molecules. The success of treatment with these drugs prompted the development of molecular-targeted drugs for systemic lupus erythematosus. However, systemic lupus erythematosus is a disease with high heterogeneous immune abnormalities, and diverse cells or molecules can be treatment targets. Thus, the identification of subpopulations based on immune abnormalities is ess ...[more]

PMID: 37371540

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Project description:Background: Accumulating evidence suggests that differentially expressed non-coding circular RNAs (circRNAs) play critical roles in the progress of autoimmune diseases. However, the role of circRNAs in systemic lupus erythematosus (SLE) remains unclear. Methods: We initially used next-generation sequencing (NGS) to comprehensively analyze circRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from 10 SLE patients, stratified by their disease activity characteristics (stable or active SLE), and 10 healthy controls (HCs). Candidate circRNAs identified were first validated by quantitative reverse-transcription (qRT)-PCR in PBMC samples from a training-phase cohort of five SLE patients and five HCs. The significantly dysregulated circRNAs were then confirmed by qRT-PCR in a validation cohort of 23 SLE patients and 21 HCs, and in an external validation cohort with 64 SLE patients, 58 HCs, and 50 patients with rheumatoid arthritis (RA). In addition, we conducted bioinformatics analysis and western blotting investigating the relationships between the candidate circRNAs and SLE progression. Results: Multilayer integrative analysis of circRNA regulation showed that 84 circRNAs were upregulated and 30 were downregulated in patients with SLE compared with HCs. We then analyzed the intersection of these differentially expressed circRNAs in an SLE-stable cohort, an SLE-active cohort, and HCs. This enabled us to narrow down dysregulated circRNAs to 15 upregulated circRNAs. Only hsa_circ_0000479 was significantly upregulated in PBMCs of patients with SLE compared with HCs (P < 0.05). Furthermore, the diagnostic potential of hsa_circ_0000479 expression to distinguish SLE patients from HCs and RA patients was also significantly increased in the validation-phase and external-validation-phase cohorts (P < 0.05). When distinguishing SLE patients from HCs, the diagnostic specificities of hsa_circ_0000479 were 0.619 and 1.0 in two validation cohorts, respectively (AUCs = 0.731 and 0.730, respectively). It was also significantly increased in either stable SLE patients or active SLE patients compared with HCs in these two cohorts (P < 0.05). We also used bioinformatics analysis to show that hsa_circ_0000479 regulates SLE progression by modulating metabolic pathways and the Wnt signaling pathway. Western blotting revealed that the expression of Wnt-16 protein was significantly decreased in SLE. Conclusion: Our results suggest that hsa_circ_0000479 has potential as a novel biomarker for the diagnosis of SLE.

Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs. However, the current SLE-related biomarkers still lack sufficient sensitivity, specificity and predictive power for clinical application. Thus, it is significant to explore new immune-related biomarkers for SLE diagnosis and development.MethodsWe obtained seven SLE gene expression profile microarrays (GSE121239/11907/81622/65391/100163/45291/49454) from the GEO database. First, differentially expressed genes (DEGs) were screened using GEO2R, and SLE biomarkers were screened by performing WGCNA, Random Forest, SVM-REF, correlation with SLEDAI and differential gene analysis. Receiver operating characteristic curves (ROCs) and AUC values were used to determine the clinical value. The expression level of the biomarker was verified by RT‒qPCR. Subsequently, functional enrichment analysis was utilized to identify biomarker-associated pathways. ssGSEA, CIBERSORT, xCell and ImmuCellAI algorithms were applied to calculate the sample immune cell infiltration abundance. Single-cell data were analyzed for gene expression specificity in immune cells. Finally, the transcriptional regulatory network of the biomarker was constructed, and the corresponding therapeutic drugs were predicted.ResultsMultiple algorithms were screened together for a unique marker gene, MX2, and expression analysis of multiple datasets revealed that MX2 was highly expressed in SLE compared to the normal group (all P < 0.05), with the same trend validated by RT‒qPCR (P = 0.026). Functional enrichment analysis identified the main pathway of MX2 promotion in SLE as the NOD-like receptor signaling pathway (NES=2.492, P < 0.001, etc.). Immuno-infiltration analysis showed that MX2 was closely associated with neutrophils, and single-cell and transcriptomic data revealed that MX2 was specifically expressed in neutrophils. The NOD-like receptor signaling pathway was also remarkably correlated with neutrophils (r >0.3, P < 0.001, etc.). Most of the MX2-related interacting proteins were associated with SLE, and potential transcription factors of MX2 and its related genes were also significantly associated with the immune response.ConclusionOur study found that MX2 can serve as an immune-related biomarker for predicting the diagnosis and disease activity of SLE. It activates the NOD-like receptor signaling pathway and promotes neutrophil infiltration to aggravate SLE.

Dataset Information

Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

Publications

Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

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