The Immune Landscape and Molecular Subtypes of Pediatric Crohn’s Disease: Results from In Silico Analysis

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.