Identification of shared T-cell pathways in the pathogenesis of atopic dermatitis and inflammatory bowel disease
Grantee: Francesca Capon, Leadership Chair in Genetic Medicine, University of British Columbia
Amount: DKK 2,116,583
Grant category: Serendipity Grants
Year: 2025
Geography: Canada
Francesca Capon unexpectedly discovered that deleterious TCF3 mutations cause a severe form of atopic dermatitis (AD) associated with inflammatory bowel disease (IBD). By querying large-scale genetic repositories, the project also observed that common TCF3 alleles are associated with susceptibility to AD and IBD in the general population. TCF3 encodes a transcription factor that plays a key role in T cell differentiation. Thus, the project hypothesizes that TCF3 mutations cause abnormal T cell activation, leading to skin and gut inflammation. Given severe AD is a risk factor for IBD, it is further proposed that the study of TCF3 mutations will shed new light on mechanisms that may underpin both conditions.
The aim of the study is to validate the involvement of TCF3 in the pathogenesis of AD and IBD. This will be achieved by identifying the immune pathways that are altered by TCF3 dysfunction in skin and gut. The plan integrates:
i) in-vitro studies to determine the impact of TCF3 mutations on protein function
ii) immune phenotyping of T cells from individuals harbouring TCF3 mutations
iii) in-silico analyses to define transcriptional networks driven by TCF3
The project expects to identify TCF3-dependent pathways contributing to AD and IBD pathogenesis. This will shed new light on shared disease mechanisms with potential to inform targeted treatment of individuals affected by both conditions.