A team led by Dr. Jingnan Li and Dr. Ji Li at Peking Union Medical College Hospital, in collaboration with Associate Professor Xiaohuan Guo and Academician Ye-Guang Chen at Tsinghua University, published findings on June 17 in the journal Immunity & Inflammation that detail new insights into the molecular mechanisms underlying colonic lesion formation in Cronkhite-Canada syndrome (CCS).
CCS is a rare, non-hereditary hamartomatous polyposis syndrome marked by diffuse gastrointestinal polyposis and distinctive ectodermal changes such as alopecia, nail dystrophy, skin hyperpigmentation, diarrhea, malabsorption, and weight loss. Since its first description in 1955, the cause of CCS has remained unclear. Unlike hereditary syndromes like Peutz–Jeghers or juvenile polyposis syndrome, CCS does not have identifiable germline pathogenic mutations. While autoimmune involvement had been suspected based on clinical observations, the specific features of immune dysregulation driving colonic hamartoma formation were previously unknown.
The research team conducted single-cell transcriptomic analysis on colonic biopsy samples from CCS patients and healthy controls. Their results showed extensive epithelial remodeling in CCS patients compared to healthy individuals. Goblet cells were notably hyperplastic with increased expression of mucin genes including MUC2, MUC4, MUC5AC, and MUC5B. An inflammatory subset of colonic epithelial cells characterized by high lipocalin-2 (LCN2) expression was also significantly increased in CCS samples.
Further investigation pointed to an altered immune microenvironment as a driver for these abnormalities. TNF-α-producing CD4+ T cells were expanded in the intestines of CCS patients relative to controls. IL-1β-secreting macrophages exhibited abnormal spatial distribution alongside hyperplastic goblet cells. Analysis suggested a cascade where TNF-α from CD4+ T cells promoted monocyte conversion into IL-1β-secreting macrophages; IL-1β then stimulated intestinal epithelial mucus secretion and prostaglandin E₂ (PGE₂) production; PGE₂ further promoted IL-1β production by macrophages—creating a self-amplifying feedback loop thought to drive persistent mucus hypersecretion and polyp formation.
To confirm these findings, an independent cohort was examined: active CCS patients had elevated serum TNF-α levels compared to healthy controls; immunohistochemistry confirmed abnormal mucin secretion consistent with predictions from sequencing data; patients in remission showed reduced TNF-α levels and less pronounced mucin abnormalities.
"The identification of the TNF-α/IL-1β/PGE₂ axis as a driver of mucus accumulation and hamartoma formation provides a theoretical basis for treating refractory CCS with existing biologics, such as anti-TNF-α antibodies (e.g., infliximab) or anti-IL-1 agents (e.g., anakinra)," the authors conclude. "Future clinical trials are needed to evaluate the efficacy of such targeted immunotherapies in CCS patients."
