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Hirschsprung\u2010associated enterocolitis (HAEC) is a significant and life\u2010threatening complication of HSCR, affecting up to 60% of patients. Animal models of endothelin receptor B (\n                    <jats:italic>EdnrB<\/jats:italic>\n                    ) mutation reliably model human HSCR and HAEC. We previously demonstrated intestinal dysbiosis and a gut\u2010specific deficiency of B\u2010lymphocyte\u2013produced secretory IgA (sIgA), the primary effector molecule of mucosal immunity, in mice with homozygous neural crest cell\u2013conditional deletion of\n                    <jats:italic>EdnrB<\/jats:italic>\n                    (\n                    <jats:italic>\n                      EdnrB\n                      <jats:sup>NCC<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ). To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B\u2010lymphocyte development and function. Expression of the endothelin axis components [endothelin\u20101 (\n                    <jats:italic>ET\u20101<\/jats:italic>\n                    ), endothelin\u20103 (\n                    <jats:italic>ET\u20103<\/jats:italic>\n                    ), endothelin receptor A (\n                    <jats:italic>EdnrA<\/jats:italic>\n                    ),\n                    <jats:italic>EdnrB<\/jats:italic>\n                    ] were determined over a developmental time course. B\u2010lymphocyte survival and Ig production were assayed\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Polymeric Ig receptor (pIgR)\u2013mediated IgA transport into the intestinal lumen was interrogated. We found endothelin axis component (\n                    <jats:italic>EdnrA, EdnrB, ET\u20101, ET\u20103<\/jats:italic>\n                    ) expression in developing extramedullary hematopoietic organs and that some splenic B lymphocytes express\n                    <jats:italic>EdnrB<\/jats:italic>\n                    . Splenic B lymphocytes from\n                    <jats:italic>\n                      EdnrB\n                      <jats:sup>NCC<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed no intrinsic defect in survival\n                    <jats:italic>vs<\/jats:italic>\n                    . wild\u2010type (WT) B lymphocytes.\n                    <jats:italic>In vitro<\/jats:italic>\n                    stimulation of splenic B lymphocytes demonstrated decreased IgA, IgG, and IgM production in\n                    <jats:italic>\n                      EdnrB\n                      <jats:sup>NCC<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>vs<\/jats:italic>\n                    . WT mice. Additionally, small intestinal pIgR was decreased \u223c50% in\n                    <jats:italic>\n                      EdnrB\n                      <jats:sup>NCC<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. These results suggest an intrinsic B\u2010lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the\n                    <jats:italic>\n                      EdnrB\n                      <jats:sup>NCC<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    model of HAEC. Our 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. Finally, our results suggest targeting the dysbiotic microbiome and pIgR\u2010mediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.\u2014Medrano, G., Cailleux, F., Guan, P., Kuruvilla, K., Barlow\u2010Anacker, A. J., Gosain, A. B\u2010lymphocyte\u2013intrinsic and \u2013extrinsic defects in secretory immunoglobulinA production in the neural crest\u2013conditional deletion of endothelin receptor B model of Hirschsprung\u2010associated enterocolitis. FASEB J. 33, 7615\u20137624 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201801913r","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T18:11:12Z","timestamp":1553537472000},"page":"7615-7624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["B\u2010lymphocyte\u2013intrinsic and \u2013extrinsic defects in secretory immunoglobulin A production in the neural crest\u2013conditional deletion of endothelin receptor B model of Hirschsprung\u2010associated enterocolitis"],"prefix":"10.1096","volume":"33","author":[{"given":"Giuliana","family":"Medrano","sequence":"first","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery University of Tennessee Health Sciences Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Cailleux","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery University of Tennessee Health Sciences Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peihong","family":"Guan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery University of Tennessee Health Sciences Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korah","family":"Kuruvilla","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery University of Tennessee Health Sciences Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Barlow-Anacker","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankush","family":"Gosain","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery University of Tennessee Health Sciences Center Memphis Tennessee USA"},{"name":"Children's Foundation Research Institute Le Bonheur Children's Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.149"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-017-4065-8"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-016-3862-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0128822"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0543"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.05.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(96)00276-2"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-005-0015-3"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)90077-G"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2007.9"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.33.6.801"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/S0022-3468(89)80566-4","article-title":"The pathophysiology of Hirschsprung's-associated enterocolitis: importance of histologic correlates","volume":"24","author":"Teitelbaum D. 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