Abstract Text: Aberrant TGF-β signaling underlies the pathogenesis of severe congenital disorders associating developmental defects with or without immune dysregulation, including Loeys–Dietz syndrome (LDS). We have recently identified IPO8 deficiency as cause of a connective tissue disorder largely overlapping with LDS. IPO8 is a member of the β-karyopherin family, the largest group of nuclear transport receptors. We have shown that IPO8 plays a critical role during early stage of development in zebrafish by controlling phospho-SMAD nuclear translocation and TGF-β/BMP-dependent transcription. Here we report increased prevalence of treatment-resistant gastrointestinal diseases, recurrent pulmonary infections and atopic diseases including asthma, dermatitis and allergies in IPO8 deficient patients. In addition to eosinophilia, multiomics approaches combining mass cytometry, single cell transcriptomics and plasma proteomics identified altered composition of B cell and myeloid compartment with peripherical proinflammatory signature in IPO8 deficient patients. To investigate the direct intrinsic effects of IPO8 loss, we generated a full knock-out mouse model using CRISPR/Cas9 editing. Pointing to spontaneous local inflammation, we found increased frequency of activated eosinophils in the small intestine of Ipo8-/- mice. Ipo8-/- intestinal organoids showed defective SMADs translocation and increased expression of pro-inflammatory immune mediators. Overall, our data show that Ipo8-/- mice are a valid model to study how dysregulation of the TGF-β signaling dependent on IPO8 loss triggers local intestinal eosinophilic activation and immune dysregulation.
