The Role of IgE in Crohn's Disease by Impairing the Capacity of Plasmacytoid Dendritic Cells to Generate FOXP3 Tregs.

Background: A causal relationship between Crohn's disease (CD) and asthma is reported, but the underlying mechanisms are not fully understood. We sought to investigate the role of IgE and IgE-mediated pathways in the pathophysiology of CD.

Methods: 20 CD patients, 10 allergic patients without inflammatory bowel disease, and 10 healthy donors (HD) were included in the study. Total serum IgE was quantified by ELISA. Circulating IgE and FcεRIα immune cells, as well as specific CD4 T cell populations, were determined by flow cytometry. Gene set enrichment signatures from available single-cell (sc)RNAseq datasets of the intestine from CD patients were analyzed. Purified plasmacytoid dendritic cells (pDCs) from CD patients were cocultured with naïve CD4 T cells to assess Tregs generation.

Results: CD patients, similar to allergic non-CD patients, displayed significantly higher numbers of circulating IgE or FcεRIα immune cells than HD. The percentage of blood IgE or FcεRIα pDCs was significantly higher in CD than HD and similar to allergic non-CD patients. CD patients showed significantly higher numbers of effector memory CD4 T cells and lower numbers of FOXP3 Tregs than HD. scRNAseq data from CD patients confirmed that Tregs imbalance and overactivation of IgE-mediated pathways take place also in gut tissues of children and adults, suggesting IgE could interfere in the pDC-Tregs axis. In vitro functional experiments demonstrated that IgE-crosslinking on pDCs from CD patients impairs Treg generation, which was restored by the anti-IgE mAb omalizumab.

Conclusions: IgE might play an unprecedented role in CD by impairing the capacity of pDCs to generate Tregs, which could represent a novel mechanism contributing to CD to be exploited for alternative therapeutic interventions.