Single-Cell RNA and ATAC Sequencing Reveal Hemodialysis-Related Immune Dysregulation of Circulating Immune Cell Subpopulations

Abstract

BackgroundAn increased risk of infection, malignancy, and cardiovascular diseases in maintenance hemodialysis patients is associated with hemodialysis-related immunity disturbances. Although defects in T-lymphocyte-dependent immune responses and preactivation of antigen-presenting cells have been documented in hemodialysis patients, the effects of long-term hemodialysis on the transcriptional program and chromosomal accessibility of circulating immune cell subpopulations remain poorly defined.MethodsWe integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to characterize the transcriptome profiles of peripheral mononuclear cells (PBMCs) from healthy controls and maintenance hemodialysis patients. Validation of differentially expressed genes in CD4+ T cells and monocytes were performed by magnetic bead separation and quantitative real-time PCR.ResultsWe identified 16 and 15 PBMC subgroups in scRNA-seq and scATAC-seq datasets, respectively. Hemodialysis significantly suppressed the expression levels of T cell receptor (TCR) genes in CD4+ T cell subsets (e.g., TRAV4, CD45, CD3G, CD3D, CD3E) and major histocompatibility complex II (MHC-II) pathway-related genes in monocytes (HLA-DRB1, HLA-DQA2, HLA-DQA1, HLA-DPB1). Downstream pathways of TCR signaling, including PI3K-Akt-mTOR, MAPK, TNF, and NF-κB pathways, were also inhibited in CD4+ T cell subpopulations during the hemodialysis procedure. Hemodialysis altered cellular communication patterns between PBMC subgroups, particularly TGF-TGFBR, HVEM-BTLA, and IL16-CD4 signalings between CD4+ T cells and monocytes. Additionally, we found that hemodialysis inhibited the expression of AP-1 family transcription factors (JUN, JUND, FOS, FOSB) by interfering with the chromatin accessibility profile.ConclusionsOur study provides a valuable framework for future investigations of hemodialysis-related immune dysregulation and identifies potential therapeutic targets for reconstituting the circulating immune system in maintenance hemodialysis patients.

Definition of regulatory elements and transcription factors controlling immune cell gene expression at single cell resolution using single nucleus ATAC-seq

“…This fraction was relatively low compared to that reported for human (in kidney; Muto et al, 2021). It might originate from the fact that the pig genome is not annotated as well as that of human or that this is the characteristic of immune cells compared to tissues; however, we detected much higher TSS enrichment scores [average was 17.99 (Supplementary Fig 1B-E)] than that of human PBMC snATAC-seq whose average is 12.55 (Wu et al, 2022). Our two replicates showed high similarity and were integrated into a dataset of 17,207 nuclei and grouped into 35 clusters.…”

Alteration of Thyroid Hormones in Mouse Models of Alzheimer’s Disease and Aging

“…It plays a significant role in the adaptive immune process. As part of the TCR complex, it delivers TCR-mediated signals followed by the activation of downstream signaling pathways [36]. Therefore, immune cell infiltration of the thyroid is a potential underlying mechanism of the alteration of THs in AD and aging.…”

Das Immunsystem des kritisch Kranken

“…Hämodialyse auf die T-Zell-Funktion und kamen zu dem Schluss, dass rezidivierende Hämodialysen zu einer Erschöpfung der T-Zell-Aktivität führen und somit zur Immunsuppression beitragen können [19]. In einer weiteren Studie von Wu et al konnte ebenfalls eine herunterregulierte mHLA-DR-Expression bei Hämodialysepatienten nachgewiesen werden [20]. Unter anderem zeigte sich auch ein Zusammenhang zwischen Transfusionen von Erythrozyten und einer anschließend gehemmten T-Zell-Proliferation sowie einer eingeschränkten Funktion von Neutrophilen [21].…”