Abstract
Renal transplantation is currently the most effective treatment for end-stage renal disease. However, chronic antibody-mediated rejection (cABMR) remains a serious obstacle for the long-term survival of patients with renal transplantation and a problem to be solved. At present, the role and mechanism underlying immune factors such as T- and B- cell subsets in cABMR after renal transplantation remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood monocytes (PBMCs) from cABMR and control subjects was performed to define the transcriptomic landscape at single-cell resolution. A comprehensive scRNA-seq analysis was performed. The results indicated that most cell types in the cABMR patients exhibited an intense interferon response and release of proinflammatory cytokines. In addition, we found that the expression of MT-ND6, CXCL8, NFKBIA, NFKBIZ, and other genes were up-regulated in T- and B-cells and these genes were associated with pro-inflammatory response and immune regulation. Western blot and qRT-PCR experiments also confirmed the up-regulated expression of these genes in cABMR. GO and KEGG enrichment analyses indicated that the overexpressed genes in T- and B-cells were mainly enriched in inflammatory pathways, including the TNF, IL-17, and Toll-like receptor signaling pathways. Additionally, MAPK and NF-κB signaling pathways were also involved in the occurrence and development of cABMR. This is consistent with the experimental results of Western blot. Trajectory analysis assembled the T-cell subsets into three differentiation paths with distinctive phenotypic and functional prog rams. CD8 effector T cells and γδ T cells showed three different differentiation trajectories, while CD8_MAI T cells and naive T cells primarily had two differentiation trajectories. Cell-cell interaction analysis revealed strong T/B cells and neutrophils activation in cABMR. Thus, the study offers new insight into pathogenesis and may have implications for the identification of novel therapeutic targets for cABMR.
Highlights
End-stage renal disease (ESRD) is one of the major causes of concern for human health
We found that differentially expressed genes (DEGs) in gd T cells, CD8 effector T cells, and CD8_MAI T cells were up-regulated in the chronic antibody-mediated rejection (cABMR) group which included MT-ND6, CXCL8, S100A9, NFKBIA, NFKBIZ, TNFAIP3, CXCR4, ZFP36, PMAIP1, DUSP10, FOS, JUN, and CCL4L2 (Figure 4)
Genes involved in the regulation of IL-17 signaling, including CXCL8, S100A9, NFKBIA, S100A8, TNFAIP3, FOS, JUND, PTGS2, and FOSB, were up-regulated in cABMR; Interestingly, we found activation of FoxO signaling in naive B-cells and its involvement in cABMR
Summary
End-stage renal disease (ESRD) is one of the major causes of concern for human health. The most effective treatment is renal transplantation, rejection remains a major threat and is a primary independent risk factor affecting the long-term survival of the transplanted kidney [1, 2]. CABMR is a serious threat to the long-term survival of the transplanted kidney which needs attention [3, 4]. Some studies show that early intervention with ABMR can improve graft survival [8, 9]. It is important to understand the host immune response during the disease to promote the design of the prognostic and early diagnostic markers, which can prevent the occurrence of cABMR in patients after kidney transplantation and to facilitate the design of appropriate appropriate therapeutic interventions to prevent graft loss
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