2022, Vol. 26 ›› Issue (30): 4806-4811

Pathogenesis of intestinal acute graft-versus-host disease after haploid hematopoietic stem cell transplantation

Yu Manya1, Kong Fansheng2, Zhang Jie2, Xu Jie2, Cui Xing2   

Abstract: BACKGROUND: Acute graft-versus-host disease is one of the most common life-threatening complications of allogeneic hematopoietic stem cell, caused by the attack of donor immunoreactive T cells on healthy recipient tissue. The current treatment plan is not effective. Long non-coding RNAs (lncRNAs) are involved in many biological processes such as immune response, but their roles in acute graft-versus-host disease remain unclear and need to be further studied.  
OBJECTIVE: To construct profiles of differentially expressed lncRNAs and differentially expressed mRNAs of intestinal acute graft-versus-host disease and predict their possible roles and mechanisms.
METHODS:   Peripheral blood mononuclear cells from four patients with intestinal acute graft-versus-host disease after haploidentical hematopoietic stem cell transplantation and four healthy volunteers were collected for high-throughput sequencing. GO and KEGG enrichment analyses were performed on the differentially expressed mRNAs. According to the dynamic change of gene expression signal value, the differential lncRNA-mRNA co-expression network was constructed. Based on the different regulatory mechanisms of lncRNA on downstream target genes, the target genes regulated by cis or trans regulation and competitive endogenous RNA mechanisms were predicted, respectively. Cytoscape was used to construct the gene interaction networks. The possible effects and related mechanisms of differentially expressed lncRNAs were predicted through functional analysis of their target genes.  
RESULTS AND CONCLUSION: There are 1 311 lncRNAs and 3 283 mRNAs differentially expressed in the peripheral blood mononuclear cells of patients with intestinal acute graft-versus-host disease. GO and KEGG analyses indicated that these differentially expressed mRNAs were involved in interleukin-18 or interleukin-1 mediated signaling pathway, AP-1 complex, megakaryocyte differentiation, and tumor necrosis factor signaling pathway, which were closely related to intestinal inflammatory response and hematopoietic ability of bone marrow. Cis-and trans-regulated genes of differentially expressed lncRNAs include some inflammation-related molecules, such as ZEB2, CDK6, CEACAM1, and CXCL1. The pathways regulated by differentially expressed lncRNAs via competitive endogenous RNA mechanism mainly include PI3K/Akt pathway and Notch pathway, which are related to the activation of T cells and the homeostasis of intestinal stem cells. It is concluded that differentially expressed lncRNAs are essential in the pathogenesis and progression of intestinal acute graft-versus-host disease via regulating the expression of inflammation-related molecules, T cell-mediated immune response, and the homeostasis of intestinal stem cells, and may become novel targets for the diagnosis and treatment of intestinal acute graft-versus-host disease.
Key words: acute graft-versus-host disease, intestine, lncRNA, mRNA, competitive endogenous RNA, cis-regulation, trans-regulation