Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways.
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Antigens, CD; Apyrase; B-Lymphocytes; Cell Death; Cellular Microenvironment; Child; Cohort Studies; Colon; Dendritic Cells; Dipyridamole; Endothelial Cells; Epithelial Cells; Fibroblasts; Gene Expression Regulation; Genetic Predisposition to Disease; Homeostasis; Humans; Immunoglobulin G; Immunologic Memory; Inflammation; Inflammatory Bowel Diseases; Interferon Type I; Intestinal Mucosa; Macrophages; Methylprednisolone; Myeloid Cells
CASP7; CD39; PDE4B; TNF; cAMP; dipyridamole; pediatric-onset colitis and IBD; platelet; risk genes; single-cell RNA expression
Huang, B., Chen, Z., Geng, L., Wang, J., Liang, H., Cao, Y., Chen, H., Huang, W., Su, M., Wang, H., Xu, Y., Liu, Y., Lu, B., Xian, H., Li, H., Li, H., Ren, L., Xie, J., Ye, L., Wang, H., Zhao, J., Chen, P., Zhang, L., Zhao, S., Zhang, T., Xu, B., Che, D., Si, W., Gu, X., Zeng, L., Wang, Y., Li, D., Zhan, Y., Delfouneso, D., Lew, A. M., Cui, J., Tang, W., Zhang, Y., Gong, S., Bai, F., Yang, M., Zhang, Y. Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways. Cell 179, 1160-1176 (2019).