Children with very early onset IBD (VEO-IBD) show life-threatening diseases that often fail to respond to conventional therapies. To explore genetic causes of VEO-IBD, we have analyzed one of the largest international cohorts using next-generation sequencing. In this screen, we have unraveled germline CD33 mutations as a novel cause for VEO-IBD. Here, we propose to employ sophisticated human disease models (induced pluripotent stem cells, CRISPR/Cas9-engineered T cells, humanized mice) to decipher the molecular mechanisms of immune dysregulations caused by CD33 deficiency. The better understanding of CD33 biology may help to define new therapeutic strategies for VEO-IBD patients but also common immune-related diseases, hematological malignancies and neurodegenerative disorders.
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