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Single-cell RNA-sequencing reveals distinct immune cell subsets and signaling pathways in IgA nephropathy.

ABSTRACT: IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally. Increasing evidence suggests the importance of host immunity in the development of IgAN, but its dynamics during the early stage of IgAN are still largely unclear. Here we successfully resolved the early transcriptomic changes in immune cells of IgAN by conducting single-cell RNA-sequencing (scRNA-seq) with peripheral blood mononuclear cells. The differentially expressed genes (DEGs) between control and IgAN were predominantly enriched in NK cell-mediated cytotoxicity and cell killing pathways. Interestingly, we discovered that the number and cytotoxicity of NK cells are significantly reduced in IgAN patients, where both the number and marker genes of NK cells were negatively associated with the clinical parameters, including the levels of urine protein creatinine ratio (UPCR), serum galactose-deficient IgA1 and IgA. A distinctive B cell subset, which had suppressed NFκB signaling was predominantly in IgAN and positively associated with disease progression. Moreover, the DEGs of B cells were enriched in different viral infection pathways. Classical monocytes also significantly changed in IgAN and a monocyte subset expressing interferon-induced genes was positively associated with the clinical severity of IgAN. Finally, we identified vast dynamics in intercellular communications in IgAN. We dissected the immune landscape of IgAN at the single-cell resolution, which provides new insights in developing novel biomarkers and immunotherapy against glomerulonephritis.

SUBMITTER: Zeng H

PROVIDER: S-EPMC8665497 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide. However, the molecular events underlying IgAN remain to be fully elucidated. This study aimed to identify novel biomarkers of IgAN through bioinformatics analysis and elucidate the possible molecular mechanism.MethodsBased on the microarray datasets GSE93798 and GSE37460 downloaded from the Gene Expression Omnibus database, the differentially expressed genes (DEGs) between IgAN samples and normal controls were identified. Using the DEGs, we further performed a series of functional enrichment analyses. Protein-protein interaction (PPI) networks of the DEGs were constructed using the STRING online search tool and were visualized using Cytoscape. Next, hub genes were identified and the most important module among the DEGs, Biological Networks Gene Ontology tool (BiNGO), was used to elucidate the molecular mechanism of IgAN.ResultsIn total, 148 DEGs were identified, comprising 53 upregulated genes and 95 downregulated genes. Gene Ontology (GO) analysis indicated that the DEGs for IgAN were mainly enriched in extracellular exosome, region and space, fibroblast growth factor stimulus, inflammatory response, and innate immunity. Module analysis showed that genes in the top 1 significant module of the PPI network were mainly associated with innate immune response, integrin-mediated signaling pathway and inflammatory response. The top 10 hub genes were constructed in the PPI network, which could well distinguish the IgAN and control group in monocyte and tissue samples. We finally identified the integrin subunit beta 2 (ITGB2) and Fc fragment of IgE receptor Ig (FCER1G) genes that may play important roles in the development of IgAN.ConclusionsWe identified key genes along with the pathways that were most closely related to IgAN initiation and progression. Our results provide a more detailed molecular mechanism for the development of IgAN and novel candidate gene targets of IgAN.

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Single-cell RNA-sequencing reveals distinct immune cell subsets and signaling pathways in IgA nephropathy.

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