Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease
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-...
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| description | 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. |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0128822</identifier><identifier>PMID: 26061883</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antigen presentation ; B cells ; B-Lymphocytes - metabolism ; Cell Movement ; Cell-mediated immunity ; Clonal deletion ; Colon ; Crohn's disease ; Crohns disease ; Defects ; Disease Models, Animal ; Disease susceptibility ; Endothelin ; Endothelins ; Enterocolitis ; Enterocolitis - etiology ; Enterocolitis - immunology ; Etiology ; Gene Deletion ; Germinal centers ; Hindgut ; Hirschsprung Disease - complications ; Hirschsprung Disease - genetics ; Hirschsprung Disease - immunology ; Humans ; Immune system ; Immunity ; Immunity (Disease) ; Immunity, Cellular ; Immunoglobulin A ; Immunoglobulin A - metabolism ; Immunoglobulin M ; Inflammatory bowel disease ; Intestinal Mucosa - growth & development ; Intestinal Mucosa - immunology ; Leukocyte migration ; Ligands ; Lymphocytes ; Lymphocytes B ; Lymphopenia ; Medicine ; Mice ; Mucosal immunity ; Mutants ; Mutation ; Neural crest ; Neural Crest - immunology ; Neural Crest - physiology ; Neurosciences ; Organs ; Patches (structures) ; Public health ; Pulp ; Receptor, Endothelin B - genetics ; Red pulp ; Respiratory tract ; Rodents ; Small intestine ; Spleen ; Surgery</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0128822</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”) Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-10dddec045b3c5f67778cc35fb0062702d93c0fe6641cebbe735f87cb41809de3</citedby><cites>FETCH-LOGICAL-c692t-10dddec045b3c5f67778cc35fb0062702d93c0fe6641cebbe735f87cb41809de3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465674/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465674/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26061883$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gosain, Ankush</creatorcontrib><creatorcontrib>Barlow-Anacker, Amanda J</creatorcontrib><creatorcontrib>Erickson, Chris S</creatorcontrib><creatorcontrib>Pierre, Joseph F</creatorcontrib><creatorcontrib>Heneghan, Aaron F</creatorcontrib><creatorcontrib>Epstein, Miles L</creatorcontrib><creatorcontrib>Kudsk, Kenneth A</creatorcontrib><title>Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Animals</subject><subject>Antigen presentation</subject><subject>B cells</subject><subject>B-Lymphocytes - metabolism</subject><subject>Cell Movement</subject><subject>Cell-mediated immunity</subject><subject>Clonal deletion</subject><subject>Colon</subject><subject>Crohn's disease</subject><subject>Crohns disease</subject><subject>Defects</subject><subject>Disease Models, Animal</subject><subject>Disease susceptibility</subject><subject>Endothelin</subject><subject>Endothelins</subject><subject>Enterocolitis</subject><subject>Enterocolitis - etiology</subject><subject>Enterocolitis - immunology</subject><subject>Etiology</subject><subject>Gene Deletion</subject><subject>Germinal centers</subject><subject>Hindgut</subject><subject>Hirschsprung Disease - complications</subject><subject>Hirschsprung Disease - genetics</subject><subject>Hirschsprung Disease - immunology</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunity (Disease)</subject><subject>Immunity, Cellular</subject><subject>Immunoglobulin A</subject><subject>Immunoglobulin A - metabolism</subject><subject>Immunoglobulin M</subject><subject>Inflammatory bowel disease</subject><subject>Intestinal Mucosa - growth & development</subject><subject>Intestinal Mucosa - immunology</subject><subject>Leukocyte migration</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphopenia</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mucosal immunity</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Neural crest</subject><subject>Neural Crest - immunology</subject><subject>Neural Crest - physiology</subject><subject>Neurosciences</subject><subject>Organs</subject><subject>Patches (structures)</subject><subject>Public health</subject><subject>Pulp</subject><subject>Receptor, Endothelin B - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26061883</pmid><doi>10.1371/journal.pone.0128822</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-06, Vol.10 (6), p.e0128822 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1687368600 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Antigen presentation B cells B-Lymphocytes - metabolism Cell Movement Cell-mediated immunity Clonal deletion Colon Crohn's disease Crohns disease Defects Disease Models, Animal Disease susceptibility Endothelin Endothelins Enterocolitis Enterocolitis - etiology Enterocolitis - immunology Etiology Gene Deletion Germinal centers Hindgut Hirschsprung Disease - complications Hirschsprung Disease - genetics Hirschsprung Disease - immunology Humans Immune system Immunity Immunity (Disease) Immunity, Cellular Immunoglobulin A Immunoglobulin A - metabolism Immunoglobulin M Inflammatory bowel disease Intestinal Mucosa - growth & development Intestinal Mucosa - immunology Leukocyte migration Ligands Lymphocytes Lymphocytes B Lymphopenia Medicine Mice Mucosal immunity Mutants Mutation Neural crest Neural Crest - immunology Neural Crest - physiology Neurosciences Organs Patches (structures) Public health Pulp Receptor, Endothelin B - genetics Red pulp Respiratory tract Rodents Small intestine Spleen Surgery |
| title | Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T16%3A19%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Impaired%20Cellular%20Immunity%20in%20the%20Murine%20Neural%20Crest%20Conditional%20Deletion%20of%20Endothelin%20Receptor-B%20Model%20of%20Hirschsprung's%20Disease&rft.jtitle=PloS%20one&rft.au=Gosain,%20Ankush&rft.date=2015-06-10&rft.volume=10&rft.issue=6&rft.spage=e0128822&rft.pages=e0128822-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0128822&rft_dat=%3Cgale_plos_%3EA417417386%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1687368600&rft_id=info:pmid/26061883&rft_galeid=A417417386&rft_doaj_id=oai_doaj_org_article_3190d835a75f4d18ae11f198f03e3b11&rfr_iscdi=true |