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Hirschsprung’s disease (HSCR) is characterized by aganglionosis from failure of neural crest cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung’s-associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hypothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contribute to enterocolitis.  EdnrB  was deleted from the neural crest ( EdnrB    NCC-/-  ) resulting in mutants with defective NCC migration, distal colonic aganglionosis and the development of enterocolitis. The mucosal immune apparatus of these mice was interrogated at post-natal day (P) 21–24, prior to histological signs of enterocolitis. We found that  EdnrB    NCC-/-   display lymphopenia of their Peyer’s Patches, the major inductive site of GI mucosal immunity.  EdnrB    NCC-/-   Peyer’s Patches demonstrate decreased B-lymphocytes, specifically IgM + IgD hi  (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation.  EdnrB    NCC-/-   animals demonstrate decreased small intestinal secretory IgA, but unchanged nasal and bronchial airway secretory IgA, indicating a gut-specific defect in IgA production or secretion. In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes,  EdnrB    NCC-/-   animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes.  EdnrB    NCC-/-   spleens are also small and show altered architecture, with decreased red pulp and a paucity of B-lymphocytes in the germinal centers and marginal zone. Taken together, these findings suggest impaired GI mucosal immunity in  EdnrB    NCC-/-   animals, with the spleen as a potential site of the defect. These findings build upon the growing body of literature that suggests that intestinal defects in HSCR are not restricted to the aganglionic colon but extend proximally, even into the ganglionated small intestine and immune cells.

Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung’s Disease