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Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension

Systemic sclerosis (SSc) is the most common connective tissue disease causing pulmonary hypertension (PAH). However, the cause and potential immune molecular events associated with PAH are still unclear. Therefore, it is particularly essential to analyze the changes in SSc-PAH–related immune cells a...

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Autores principales: Tu, Jianxin, Jin, Jinji, Chen, Xiaowei, Sun, Li, Cai, Zhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159786/
https://www.ncbi.nlm.nih.gov/pubmed/35663995
http://dx.doi.org/10.3389/fimmu.2022.868983
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author Tu, Jianxin
Jin, Jinji
Chen, Xiaowei
Sun, Li
Cai, Zhen
author_facet Tu, Jianxin
Jin, Jinji
Chen, Xiaowei
Sun, Li
Cai, Zhen
author_sort Tu, Jianxin
collection PubMed
description Systemic sclerosis (SSc) is the most common connective tissue disease causing pulmonary hypertension (PAH). However, the cause and potential immune molecular events associated with PAH are still unclear. Therefore, it is particularly essential to analyze the changes in SSc-PAH–related immune cells and their immune-related genes. Three microarray datasets (GSE22356, GSE33463, and GSE19617) were obtained by the Gene Expression Omnibus (GEO). Compared with SSc, we found neutrophils have a statistically higher abundance, while T-cell CD4 naive and T-cell CD4 memory resting have a statistically lower abundance in peripheral blood mononuclear cells (PBMCs). Moreover, the results of Gene Set Enrichment Analysis (GSEA) showed there is a differential enrichment of multiple pathways between SSc and SSc-PAH. By combining differentiated expressed genes (DEGs) and immune-related genes (IRGs), fifteen IRGs were selected. In addition, we also analyzed the first five rich Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and the most abundant Gene Ontology (GO)-molecular functional terms. Furthermore, interleukin-7 receptor (IL-7R), tyrosine–protein kinase (LCK), histone deacetylase 1 (HDAC1), and epidermal growth factor receptor (EGFR) genes were identified as hub genes via protein–protein interaction (PPI) network analysis. The Comparative Toxic Genomics Database (CTD) analysis result showed that LCK, HDAC1, and EGFR have a higher score with SSc. Coexpression network analysis confirmed that IL-7R, LCK, and HDAC1 are key genes related to immune regulation in SSc without PAH and are involved in T-cell immune regulation. Subsequently, using GSE22356 and GSE33463 as the test sets and GSE19617 as the verification set, it was verified that the mRNA expression levels of the three central genes of SSc-PAH were significantly lower than those of the SSc without PAH samples. Consistent with previous predictions, the expressions of IL-7R, LCK, and HDAC1 are positively correlated with the numbers of T-cell CD4 naive and T-cell CD4 memory, while the expressions of IL-7R and LCK are negatively correlated with the numbers of neutrophils in the peripheral blood. Therefore, this evidence may suggest that these three immune-related genes: IL-7R, LCK, and HDAC1, may be highly related to the immunological changes in SSc-PAH. These three molecules can reduce T cells in SSc-PAH PBMCs through the regulation of T-cell activation, which suggests that these three molecules may be involved in the development of SSc-PAH. Meanwhile, the low expression of IL-7R, LCK, and HDAC1 detected in the peripheral blood of SSc may indicate the possibility of PAH and hopefully become a biomarker for the early detection of SSc-PAH. Finally, 49 target miRNAs of 3 specifically expressed hub genes were obtained, and 49 mRNA–miRNA pairs were identified, which provided directions for our further research.
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spelling pubmed-91597862022-06-02 Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension Tu, Jianxin Jin, Jinji Chen, Xiaowei Sun, Li Cai, Zhen Front Immunol Immunology Systemic sclerosis (SSc) is the most common connective tissue disease causing pulmonary hypertension (PAH). However, the cause and potential immune molecular events associated with PAH are still unclear. Therefore, it is particularly essential to analyze the changes in SSc-PAH–related immune cells and their immune-related genes. Three microarray datasets (GSE22356, GSE33463, and GSE19617) were obtained by the Gene Expression Omnibus (GEO). Compared with SSc, we found neutrophils have a statistically higher abundance, while T-cell CD4 naive and T-cell CD4 memory resting have a statistically lower abundance in peripheral blood mononuclear cells (PBMCs). Moreover, the results of Gene Set Enrichment Analysis (GSEA) showed there is a differential enrichment of multiple pathways between SSc and SSc-PAH. By combining differentiated expressed genes (DEGs) and immune-related genes (IRGs), fifteen IRGs were selected. In addition, we also analyzed the first five rich Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and the most abundant Gene Ontology (GO)-molecular functional terms. Furthermore, interleukin-7 receptor (IL-7R), tyrosine–protein kinase (LCK), histone deacetylase 1 (HDAC1), and epidermal growth factor receptor (EGFR) genes were identified as hub genes via protein–protein interaction (PPI) network analysis. The Comparative Toxic Genomics Database (CTD) analysis result showed that LCK, HDAC1, and EGFR have a higher score with SSc. Coexpression network analysis confirmed that IL-7R, LCK, and HDAC1 are key genes related to immune regulation in SSc without PAH and are involved in T-cell immune regulation. Subsequently, using GSE22356 and GSE33463 as the test sets and GSE19617 as the verification set, it was verified that the mRNA expression levels of the three central genes of SSc-PAH were significantly lower than those of the SSc without PAH samples. Consistent with previous predictions, the expressions of IL-7R, LCK, and HDAC1 are positively correlated with the numbers of T-cell CD4 naive and T-cell CD4 memory, while the expressions of IL-7R and LCK are negatively correlated with the numbers of neutrophils in the peripheral blood. Therefore, this evidence may suggest that these three immune-related genes: IL-7R, LCK, and HDAC1, may be highly related to the immunological changes in SSc-PAH. These three molecules can reduce T cells in SSc-PAH PBMCs through the regulation of T-cell activation, which suggests that these three molecules may be involved in the development of SSc-PAH. Meanwhile, the low expression of IL-7R, LCK, and HDAC1 detected in the peripheral blood of SSc may indicate the possibility of PAH and hopefully become a biomarker for the early detection of SSc-PAH. Finally, 49 target miRNAs of 3 specifically expressed hub genes were obtained, and 49 mRNA–miRNA pairs were identified, which provided directions for our further research. Frontiers Media S.A. 2022-05-18 /pmc/articles/PMC9159786/ /pubmed/35663995 http://dx.doi.org/10.3389/fimmu.2022.868983 Text en Copyright © 2022 Tu, Jin, Chen, Sun and Cai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tu, Jianxin
Jin, Jinji
Chen, Xiaowei
Sun, Li
Cai, Zhen
Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title_full Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title_fullStr Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title_full_unstemmed Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title_short Altered Cellular Immunity and Differentially Expressed Immune-Related Genes in Patients With Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
title_sort altered cellular immunity and differentially expressed immune-related genes in patients with systemic sclerosis–associated pulmonary arterial hypertension
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159786/
https://www.ncbi.nlm.nih.gov/pubmed/35663995
http://dx.doi.org/10.3389/fimmu.2022.868983
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