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The Immune Landscape and Molecular Subtypes of Pediatric Crohn's Disease: Results from In Silico Analysis
Shiyu Xiao1,2, Wenhui Xie3, Yinghui Zhang1,2
1Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
Insights
This study identifies key immune cells and genes in pediatric Crohn's disease (CD), revealing a new molecular classification. This finding may lead to personalized treatments for pediatric CD patients.
Area of Science:
- Immunology
- Genetics
- Pediatric Gastroenterology
Background:
- Pediatric Crohn's disease (CD) has a unique presentation compared to adult CD.
- Immune system dysregulation is central to CD pathogenesis.
- Understanding immune cell profiles and molecular subtypes is crucial for pediatric CD management.
Purpose of the Study:
- To analyze immune cell alterations in pediatric CD.
- To identify molecular signatures and classifications for pediatric CD.
- To correlate gene expression with clinical features and immune infiltration.
Main Methods:
- RNA-sequencing data (GSE101794) from 254 treatment-naïve pediatric CD samples were analyzed.
- CIBERSORTx and weighted gene co-expression network analysis (WGCNA) were used to assess immune cell ratios and identify gene modules.
- Unsupervised K-means clustering based on hub genes was employed for molecular subtyping.
Main Results:
- M2 macrophages, CD4+ memory resting T cells, CD8+ T cells, and resting mast cells were predominant immune cells.
- Differential gene expression analysis revealed 985 upregulated and 860 downregulated genes in samples with high immune cell infiltration.
- Ten hub genes associated with CD8+ T cell infiltration were identified, correlating with earlier onset and colonic CD, leading to three molecular subtypes.
Conclusions:
- This in silico analysis provides novel insights into the immune landscape of pediatric CD.
- A new molecular classification for pediatric CD based on immune signatures has been established.
- The findings may facilitate personalized disease management and therapeutic strategies for pediatric CD.
Abstract:
Pediatric Crohn's disease (CD) presents a distinct phenotype from adult-onset disease. A dysregulated immune response is critical in CD pathogenesis; thus, it is clinically important to describe immune cell alterations and to identify a new molecular classification for pediatric CD. To this end, in this study, a RNA-seq derived dataset GSE101794-which contains the expression profiles of 254 treatment-naïve pediatric CD samples, including CIBERSORTx and weighted gene-co-expression network analysis (WGCNA)-were performed to estimate the ratio of immune cells and to identify modules and genes related to specific immune cell infiltration, respectively. Hub genes derived from WGCNA were further employed to create a molecular classification using unsupervised K-means clustering. In the pediatric CD samples, it was found that M2 macrophages, CD4+ memory resting T cells, CD8+ T cells, and resting mast cells were the most prominent immune cells in intestinal tissues. Then, 985 up-regulated genes and 860 down-regulated genes were identified in samples with high immune cell infiltration. Of these differential genes, 10 hub genes (APOA1, CYB5A, XPNPEP2, SLC1A7, SLC4A6, LIPE, G6PC, AGXT2, SLC13A1, and SOAT2) were associated with CD8+T cell infiltration. Clinically, the higher expression of these 10 hub genes was strongly associated with an earlier age of CD onset and colonic-type CD. Furthermore, based on these key genes, pediatric CD could be classified into three molecular subtypes, displaying a different immune landscape. Altogether, this in silico analysis provides a novel insight into the immune signature of pediatric CD, and a new classification of pediatric CD is presented, which may help us develop more personalized disease management and treatments for pediatric CD.
