B-lymphocyte–intrinsic and –extrinsic defects in secretory immunoglobulin A production in the neural crest–conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis

What is it about?

Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the newborn. Hirschsprung-Associated Enterocolitis (HAEC) is a significant and life-threatening complication of HSCR, impacting up to 60% of children with HAEC. HAEC has an incompletely-defined, multi-factorial etiology. Currently, the only treatment for patients with HAEC is non-specific and consists of systemic antibiotics, rectal irrigations and bowel rest. Development of a targeted therapy for HAEC has the potential to decrease mortality. We previously demonstrated intestinal dysbiosis and a gut-specific deficiency of B lymphocyte produced Secretory Immunoglobulin A (sIgA), the primary effector molecule of mucosal immunity, in mice with neural crest-conditional deletion of EdnrB (EdnrBNCC-/-) that model human HAEC. To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B lymphocyte development and function. Our results demonstrate that there appears to be an intrinsic B lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the EdnrBNCC-/- model of HAEC. These results are consistent with human HAEC observations of decreased luminal sIgA and mouse models of other inflammatory bowel diseases, in which decreased pIgR is seen in concert with a dysregulated microbiota. The current results and our prior investigations have refined our understanding of HAEC pathogenesis: ENS dysmotility (present from birth) results in microbiome dysbiosis. This precipitates intestinal barrier dysfunction and an impaired immune response, culminating in HAEC and death. Finally, our results suggest targeting the dysbiotic microbiome and pIgR-mediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.

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