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

Gosain A, Barlow-Anacker AJ, Erickson CS, Pierre JF, Heneghan AF, Epstein ML, Kudsk KA - PLoS ONE (2015)

Bottom Line: We found that EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity.In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes.EdnrBNCC-/- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America; Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America.

ABSTRACT
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 (EdnrBNCC-/-) 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 EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrBNCC-/- Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM+IgDhi (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrBNCC-/- 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, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrBNCC-/- 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 EdnrBNCC-/- 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.

No MeSH data available.


Related in: MedlinePlus

EdnrBNCC-/- animals develop intestinal inflammation in the fourth week of life.Inflammation within proximal colon and mid-colon of P26-29 EdnrBNCC+/- (Het) and EdnrBNCC-/- (Null) animals was graded using the previously published Murine Enterocolitis Grading System (Cheng, et.al., 2010). (A) There was evidence of inflammation in both the (B) proximal and (C) mid-colon of the EdnrBNCC-/- animals at the later time point. Arrows indicate inflammatory cells. Scale bar = 50 μm. (*p<0.05).
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pone.0128822.g001: EdnrBNCC-/- animals develop intestinal inflammation in the fourth week of life.Inflammation within proximal colon and mid-colon of P26-29 EdnrBNCC+/- (Het) and EdnrBNCC-/- (Null) animals was graded using the previously published Murine Enterocolitis Grading System (Cheng, et.al., 2010). (A) There was evidence of inflammation in both the (B) proximal and (C) mid-colon of the EdnrBNCC-/- animals at the later time point. Arrows indicate inflammatory cells. Scale bar = 50 μm. (*p<0.05).

Mentions: The piebald lethal mouse strain, which contains a naturally-occurring EdnrB mutation, and conventional EdnrB knockout mice experience mortality near the fourth postnatal (P) week [40,41]. We have previously confirmed a similar timing of mortality in our model of NCC conditional deletion of EdnrB, with EdnrBNCC-/- experiencing 50% mortality by P26 and 90% mortality by P32 [19]. To correlate histological evidence of colonic inflammation with this time course, we examined the distal small intestine, proximal colon and mid-colon of P21-24 and P26-29 EdnrBNCC+/- and EdnrBNCC-/- animals using the previously published Murine Enterocolitis Grading System [40] (Table 1 and Fig 1). There was evidence of inflammation in both the proximal and mid-colon of the EdnrBNCC-/- animals at P26-29. However, no inflammation was seen in the EdnrBNCC-/- animals at the early time point or in the small intestine at the later time point. Finally, no inflammation was seen in the EdnrBNCC+/- animals at either time point or anatomic location.


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

Gosain A, Barlow-Anacker AJ, Erickson CS, Pierre JF, Heneghan AF, Epstein ML, Kudsk KA - PLoS ONE (2015)

EdnrBNCC-/- animals develop intestinal inflammation in the fourth week of life.Inflammation within proximal colon and mid-colon of P26-29 EdnrBNCC+/- (Het) and EdnrBNCC-/- (Null) animals was graded using the previously published Murine Enterocolitis Grading System (Cheng, et.al., 2010). (A) There was evidence of inflammation in both the (B) proximal and (C) mid-colon of the EdnrBNCC-/- animals at the later time point. Arrows indicate inflammatory cells. Scale bar = 50 μm. (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465674&req=5

pone.0128822.g001: EdnrBNCC-/- animals develop intestinal inflammation in the fourth week of life.Inflammation within proximal colon and mid-colon of P26-29 EdnrBNCC+/- (Het) and EdnrBNCC-/- (Null) animals was graded using the previously published Murine Enterocolitis Grading System (Cheng, et.al., 2010). (A) There was evidence of inflammation in both the (B) proximal and (C) mid-colon of the EdnrBNCC-/- animals at the later time point. Arrows indicate inflammatory cells. Scale bar = 50 μm. (*p<0.05).
Mentions: The piebald lethal mouse strain, which contains a naturally-occurring EdnrB mutation, and conventional EdnrB knockout mice experience mortality near the fourth postnatal (P) week [40,41]. We have previously confirmed a similar timing of mortality in our model of NCC conditional deletion of EdnrB, with EdnrBNCC-/- experiencing 50% mortality by P26 and 90% mortality by P32 [19]. To correlate histological evidence of colonic inflammation with this time course, we examined the distal small intestine, proximal colon and mid-colon of P21-24 and P26-29 EdnrBNCC+/- and EdnrBNCC-/- animals using the previously published Murine Enterocolitis Grading System [40] (Table 1 and Fig 1). There was evidence of inflammation in both the proximal and mid-colon of the EdnrBNCC-/- animals at P26-29. However, no inflammation was seen in the EdnrBNCC-/- animals at the early time point or in the small intestine at the later time point. Finally, no inflammation was seen in the EdnrBNCC+/- animals at either time point or anatomic location.

Bottom Line: We found that EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity.In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes.EdnrBNCC-/- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America; Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America.

ABSTRACT
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 (EdnrBNCC-/-) 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 EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrBNCC-/- Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM+IgDhi (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrBNCC-/- 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, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrBNCC-/- 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 EdnrBNCC-/- 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.

No MeSH data available.


Related in: MedlinePlus