Abstract
Severe aplastic anaemia (SAA) is an autoimmune disease with immune tolerance dysfunction mediated by hyperactivated T lymphocytes that target the haematopoietic system. Numerous studies suggest that long noncoding RNAs (lncRNAs) play a significant role in almost every level of gene function/regulation. However, their specific mechanisms in SAA remain undetermined. This study is aimed at determining the role of key lncRNAs in CD8+ T lymphocytes in the mechanisms of SAA. RNA-seq was performed to detect all lncRNAs and mRNAs in peripheral CD8+ T lymphocytes from SAA patients and healthy controls. The lncRNA targets were predicted by bioinformatics, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RT-qPCR was used to verify the expression of key lncRNAs and their predicted targets. We screened lncRNA AF117829.1, which was correlated with autoimmune diseases and downregulated in CD8+ T lymphocytes, and further validated its effects on CD8+ T lymphocytes from SAA patients. We systematically described the lncRNA/mRNA expression changes in CD8+ T lymphocytes in SAA patients and assessed their possible biological functions and signalling pathways. A total of 194 lncRNAs and 2099 mRNAs were changed in SAA patients versus healthy controls. These differentially expressed lncRNAs/mRNAs were associated with organelle components, catalytic activity, the response to stimulation, signal transduction, the immune system and metabolic processes. The downregulated expression of one altered factor, lncRNA AF117829.1, in CD8+ T lymphocytes from SAA patients increased CD8+ T lymphocyte immune function by promoting RIP2 expression. lncRNA AF117829.1 overexpression in CD8+ T lymphocytes reduced perforin and granzyme B expression. The same effect was achieved with GSK583, a RIP2 kinase inhibitor. The proliferation and overactivation of CD8+ T lymphocytes, also known as cytotoxic T cells (CTLs), directly induce bone marrow (BM) failure in SAA patients, but the specific mechanism remains unclear. We found that lncRNA AF117829.1 and its target genes were associated with T cell proliferation, differentiation, and immune dysregulation and that lncRNA AF117829.1 regulated CD8+ T lymphocyte function in SAA patients by promoting RIP2 expression. These findings improve our understanding of the molecular mechanism of immune pathogenesis and provide potential targets for SAA diagnosis and treatment.
Highlights
Severe aplastic anaemia (SAA) refers to a haematological disease represented by pancytopenia in association with bone marrow (BM) hypoplasia/aplasia
Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the differentially expressed mRNAs were mainly enriched in the c-Jun N-terminal kinase (JNK), RAS, nucleotide-binding oligomerization domain 2/ receptor-interacting protein 2 (NOD2/RIP2), and mitogenactivated protein kinase (MAPK) signalling pathways
Based on our previous high-throughput sequencing results and further studies, we found that long noncoding RNAs (lncRNAs) AF117829.1 expression was notably decreased in CD8+ T lymphocytes from patients with SAA, whose function was associated with T lymphocyte proliferation and activation. lncRNAs regulate gene expression independent of protein coding and interact with protein-coding genes in various cell types through multiple processes, such as epigenetic regulation of transcription, mRNA stability, and protein localization [38]. lncRNAs have been shown to be closely related to various immune diseases [39,40,41]
Summary
Severe aplastic anaemia (SAA) refers to a haematological disease represented by pancytopenia in association with bone marrow (BM) hypoplasia/aplasia. The typical clinical symptoms of SAA comprise severe anaemia, infection, and bleeding/bruising; SAA is an acute condition that progresses rapidly [1]. If effective treatment is not given in time, patients often die from severe bleeding or infection. Immunosuppressive therapy (IST) and haematopoietic therapy based on antithymocyte globulin, antilymphocyte globulin (ATG/ALG), and cyclosporine A (CsA) have been widely used in the treatment of this disease with an effective rate of up to more than 70%, but these approaches are ineffective in nearly 30% of SAA patients, some of which die from the disease [2]. 10% of patients in remission may relapse [2]. Further exploration of the immune pathogenesis of SAA is of great significance for determining new treatment directions and establishing effective diagnostic and prognostic indicators
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