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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Inflammatory bowel disease and mutations affecting the interleukin-10 receptor
Erik-Oliver Glocker1, Daniel Kotlarz, Kaan Boztug
1Department of Immunology, Royal Free Hospital and University College London, United Kingdom.
The New England Journal of Medicine
|November 6, 2009
Summary
Mutations in interleukin-10 receptor (IL-10R) genes cause early-onset inflammatory bowel disease by disrupting immune regulation. Stem cell transplantation offered disease remission in one patient, highlighting a potential therapeutic avenue.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- The precise molecular etiology of inflammatory bowel disease (IBD) remains largely elusive.
- Early-onset IBD presents a significant clinical challenge, often with severe manifestations.
Observation:
- Genetic-linkage analysis and candidate-gene sequencing were performed on families with early-onset IBD.
- Functional assays in patient-derived cells and hematopoietic stem-cell transplantation were conducted.
Findings:
- Three distinct homozygous mutations in IL10RA and IL10RB genes, encoding IL-10 receptor subunits, were identified in 4 of 9 patients.
- These mutations impair interleukin-10 (IL-10) signaling, evidenced by reduced STAT3 phosphorylation.
- Defective IL-10R function leads to increased pro-inflammatory cytokine secretion, indicating a loss of immune homeostasis.
Implications:
- Mutations in IL-10 receptor subunit genes are implicated in early-onset enterocolitis characterized by hyperinflammation.
- Allogeneic hematopoietic stem-cell transplantation demonstrated efficacy, leading to disease remission in a treated patient.
- These findings underscore the critical role of the IL-10 signaling pathway in intestinal immune regulation and suggest potential therapeutic targets for IBD.
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