Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells
Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bact...
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| Veröffentlicht in: | PloS one 2017-09, Vol.12 (9), p.e0185025-e0185025 |
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| description | Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.
Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.
More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.
A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease. |
| doi_str_mv | 10.1371/journal.pone.0185025 |
| format | Article |
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Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.
More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.
A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0185025</identifier><identifier>PMID: 28934294</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Active control ; Antigens ; Autoimmune diseases ; Bacteria ; Bacteria - immunology ; Biological activity ; Biology and Life Sciences ; Biomarkers - metabolism ; Biopsy ; Care and treatment ; Celiac disease ; Celiac Disease - immunology ; Celiac Disease - microbiology ; Celiac Disease - pathology ; Cells, Cultured ; Child ; Child, Preschool ; Childhood ; Children ; CIITA protein ; Cytokines ; Dendritic cells ; Diet ; Disease control ; Epithelial cells ; Epithelium ; Female ; Gene expression ; Genes ; Genetic aspects ; Gluten ; Glutens - administration & dosage ; Histocompatibility antigen HLA ; Humans ; Immune response ; Immunology ; Inflammasomes ; Inflammatory response ; Interferon ; Interferon regulatory factor 1 ; Interferon Regulatory Factor-1 - metabolism ; Interleukin 18 ; Intestinal Mucosa - immunology ; Intestinal Mucosa - microbiology ; Intestinal Mucosa - pathology ; Intolerance ; Lymphocytes ; Lymphocytes - immunology ; Lymphocytes - microbiology ; Lymphocytes - pathology ; Male ; Medicine and Health Sciences ; Monolayers ; Mucosa ; Overexpression ; Pediatrics ; Physiological aspects ; Small intestine ; Viral infections</subject><ispartof>PloS one, 2017-09, Vol.12 (9), p.e0185025-e0185025</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Pietz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Pietz et al 2017 Pietz et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c730t-88f689aec8d361bd9108388bf70613314995323a8fc89bb63e55e9c1506f65143</citedby><cites>FETCH-LOGICAL-c730t-88f689aec8d361bd9108388bf70613314995323a8fc89bb63e55e9c1506f65143</cites><orcidid>0000-0001-6182-4423</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608296/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608296/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28934294$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-139860$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Sestak, Karol</contributor><creatorcontrib>Pietz, Grzegorz</creatorcontrib><creatorcontrib>De, Rituparna</creatorcontrib><creatorcontrib>Hedberg, Maria</creatorcontrib><creatorcontrib>Sjöberg, Veronika</creatorcontrib><creatorcontrib>Sandström, Olof</creatorcontrib><creatorcontrib>Hernell, Olle</creatorcontrib><creatorcontrib>Hammarström, Sten</creatorcontrib><creatorcontrib>Hammarström, Marie-Louise</creatorcontrib><title>Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.
Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.
More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.
A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.</description><subject>Active control</subject><subject>Antigens</subject><subject>Autoimmune diseases</subject><subject>Bacteria</subject><subject>Bacteria - immunology</subject><subject>Biological activity</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers - metabolism</subject><subject>Biopsy</subject><subject>Care and treatment</subject><subject>Celiac disease</subject><subject>Celiac Disease - immunology</subject><subject>Celiac Disease - microbiology</subject><subject>Celiac Disease - pathology</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Childhood</subject><subject>Children</subject><subject>CIITA protein</subject><subject>Cytokines</subject><subject>Dendritic cells</subject><subject>Diet</subject><subject>Disease control</subject><subject>Epithelial cells</subject><subject>Epithelium</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Gluten</subject><subject>Glutens - administration & dosage</subject><subject>Histocompatibility antigen HLA</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunology</subject><subject>Inflammasomes</subject><subject>Inflammatory response</subject><subject>Interferon</subject><subject>Interferon regulatory factor 1</subject><subject>Interferon Regulatory Factor-1 - metabolism</subject><subject>Interleukin 18</subject><subject>Intestinal Mucosa - immunology</subject><subject>Intestinal Mucosa - microbiology</subject><subject>Intestinal Mucosa - pathology</subject><subject>Intolerance</subject><subject>Lymphocytes</subject><subject>Lymphocytes - immunology</subject><subject>Lymphocytes - 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Veronika</au><au>Sandström, Olof</au><au>Hernell, Olle</au><au>Hammarström, Sten</au><au>Hammarström, Marie-Louise</au><au>Sestak, Karol</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-09-21</date><risdate>2017</risdate><volume>12</volume><issue>9</issue><spage>e0185025</spage><epage>e0185025</epage><pages>e0185025-e0185025</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.
Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.
More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.
A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28934294</pmid><doi>10.1371/journal.pone.0185025</doi><tpages>e0185025</tpages><orcidid>https://orcid.org/0000-0001-6182-4423</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-09, Vol.12 (9), p.e0185025-e0185025 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1941348471 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; SWEPUB Freely available online; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Active control Antigens Autoimmune diseases Bacteria Bacteria - immunology Biological activity Biology and Life Sciences Biomarkers - metabolism Biopsy Care and treatment Celiac disease Celiac Disease - immunology Celiac Disease - microbiology Celiac Disease - pathology Cells, Cultured Child Child, Preschool Childhood Children CIITA protein Cytokines Dendritic cells Diet Disease control Epithelial cells Epithelium Female Gene expression Genes Genetic aspects Gluten Glutens - administration & dosage Histocompatibility antigen HLA Humans Immune response Immunology Inflammasomes Inflammatory response Interferon Interferon regulatory factor 1 Interferon Regulatory Factor-1 - metabolism Interleukin 18 Intestinal Mucosa - immunology Intestinal Mucosa - microbiology Intestinal Mucosa - pathology Intolerance Lymphocytes Lymphocytes - immunology Lymphocytes - microbiology Lymphocytes - pathology Male Medicine and Health Sciences Monolayers Mucosa Overexpression Pediatrics Physiological aspects Small intestine Viral infections |
| title | Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T05%3A35%3A35IST&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=Immunopathology%20of%20childhood%20celiac%20disease-Key%20role%20of%20intestinal%20epithelial%20cells&rft.jtitle=PloS%20one&rft.au=Pietz,%20Grzegorz&rft.date=2017-09-21&rft.volume=12&rft.issue=9&rft.spage=e0185025&rft.epage=e0185025&rft.pages=e0185025-e0185025&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0185025&rft_dat=%3Cgale_plos_%3EA505755394%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=1941348471&rft_id=info:pmid/28934294&rft_galeid=A505755394&rft_doaj_id=oai_doaj_org_article_4e1e5909f99f49869d39b0bf40a3a490&rfr_iscdi=true |