Studying the intestinal microbiome as a driver for immune pathology in CTLA4 insufficient individuals and mice

Project Summary

In this project, we hypothesizes that the gut microbiome is a key determinant of phenotypic differences between affected and unaffected CTLA4 mutation carriers, and possibly also impacts on the disease expressivity. To experimentally address this hypothesis, B05 will (i) identify microbial taxa, which are differentially present in affected mutation carriers versus unaffected carriers of the same mutation by metagenomics studies; (ii) explore whether microbial dysregulation and immunopathology improves with CTLA4-Fc (abatacept) treatment; (iii) implement disease models in CTLA4+/- heterozygous mice to allow for experimental manipulations, establishing causal relationships between the observed phenotype and the microbiome. A better understanding of the interaction of microbiota with the immune system in CTLA4-insufficient patients will offer novel avenues for therapeutic interventions not only for this patient cohort.