The effect of Crohn's disease NOD2 mutations on cytokine secretion
Research type
Research Study
Full title
Determination of the effect of heterozygous Crohn's related mutations in NOD2 upon neutrophil accumulation in patients in vivo and cytokine secretion by monocytes in vitro.
IRAS ID
282430
Contact name
Andrew Smith
Contact email
Sponsor organisation
UCL
Clinicaltrials.gov Identifier
Z6364106/2020/05/23, UCL’s Data Protection Policy
Duration of Study in the UK
0 years, 11 months, 31 days
Research summary
Crohn's disease is a serious chronic inflammatory condition that predominantly affects the gastrointestinal tract and causes considerable morbidity and some mortality. It affects 1 in 500-1000 of the population and costs the NHS roughly £1 billion a year.
The underlying cause of this disease is a failure of acute inflammation which results in the delayed recruitment of neutrophil leukocytes to areas of acute inflammation in the body. The role of neutrophils is to engulf, digest and remove microbes and foreign organic material from the tissues. In Crohn’s disease faecal material that gains access to the bowel wall as a result of infection, is not cleared and this leads to a chronic granulomatous inflammation, fibrosis, structuring and fistula formation.
Acute inflammation fails in Crohn’s disease because the secretion of proinflammatory cytokines by monocytes and macrophages is impaired. Pathogen-associated molecular patterns (PAMPs) are recognized by pattern-recognition receptors (PRRs), which play a key role in innate immunity in the recognition of pathogens or of cellular injury. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), is an intracellular pattern recognition receptor, which recognizes molecules containing the specific structure called muramyl dipeptide (MDP) that is found in certain bacteria.
The binding of MDP to NOD2 activates a signal transduction pathway that results in the production of pro-inflammatory cytokines like interleukins 8 and 1β.
Three inactivating mutations in CARD15, the gene coding for NOD2, provide the strongest genetic association with Crohn’s disease. When heterozygous (one copy /cell) the risk of disease is elevated approximately 3X, but when homozygous (2 copies/cell) the risk can be increased 40X.
We have investigated the effect of homozygous mutations on acute inflammation in skin windows and on cytokine secretion from monocytes/macrophages. The effect of the heterozygous mutations on these processes is unknown and the question that we wish to address in this study.REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
20/NW/0475
Date of REC Opinion
15 Jan 2021
REC opinion
Further Information Favourable Opinion