Integrated analysis of cell-specific gene expression in peripheral blood using ISG15 as a marker of rejection in kidney transplantation

Zijian Zhang; Yan Qin; Yicun Wang; Shuai Li; Xiaopeng Hu

doi:10.3389/fimmu.2023.1153940

Integrated analysis of cell-specific gene expression in peripheral blood using ISG15 as a marker of rejection in kidney transplantation

Front Immunol. 2023 Mar 8:14:1153940. doi: 10.3389/fimmu.2023.1153940. eCollection 2023.

Authors

Zijian Zhang^{1

2}, Yan Qin^{1

2}, Yicun Wang^{1

2}, Shuai Li^{1

2}, Xiaopeng Hu^{1

2}

Affiliations

¹ Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
² Institute of Urology, Capital Medical University, Beijing, China.

Abstract

Background: Allograft kidney rejection can lead to graft dysfunction and graft loss. Protocol biopsy poses additional risk for recipients with normal renal function. The transcriptome of peripheral blood mononuclear cells (PBMCs) contains tremendous information and has potential application value for non-invasive diagnosis.

Methods: From the Gene Expression Omnibus database, we collected three datasets containing 109 rejected samples and 215 normal controls. After data filter and normalization, we performed deconvolution of bulk RNA sequencing data to predict cell type and cell-type specific gene expression. Subsequently, we calculated cell communication analysis by Tensor-cell2cell and conducted the least absolute shrinkage and selection operator (LASSO) logistic regression to screen the robust differentially expressed genes (DEGs). These gene expression levels were validated in mice kidney transplantation acute rejection model. The function of the novel gene ISG15 in monocytes was further confirmed by gene knockdown and lymphocyte-stimulated assay.

Results: The bulk RNA-seq hardly predicted kidney transplant rejection accurately. Seven types of immune cells and transcriptomic characteristics were predicted from the gene expression data. The monocytes showed significant differences in amount and gene expression of rejection. The cell-to-cell communication indicated the enrichment of antigen presentation and T cell activation ligand-receptor pairs. Then 10 robust genes were found by Lasso regression and a novel gene ISG15 remained differential expression in monocytes between rejection samples and normal control both in public data and animal model. Furthermore, ISG15 also showed a critical role in promoting the proliferation of T cells.

Conclusion: This study identified and validated a novel gene ISG15 associated with rejection in peripheral blood after kidney transplantation, which is a significant non-invasive diagnosis and a potential therapeutic target.

Keywords: graft survival; immune response; kidney transplantation; monocytes; rejection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Gene Expression Profiling
Graft Rejection* / diagnosis
Graft Rejection* / genetics
Humans
Kidney Transplantation* / adverse effects
Leukocytes, Mononuclear
Lymphocytes
Mice
Transcriptome

Substances

ISG15 protein, human

Grants and funding

This work was supported by the General Program of the National Natural Science Foundation of China (NSFC) (81970645, 82000711, 82170766) and the joint fund of the Beijing Municipal Commission of Education and Natural Science Foundation of Beijing Municipality (KZ202010025036)