CARD15 frameshift mutation in patients with CROHN disease is associated with immune dysregulation. Export

@article{citeulike:117195, abstract = {BACKGROUND: Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD). CARD15 is an intracellular receptor for bacterial lipopolysaccharides (LPS). LPS-induced activation of transfectants containing the frameshift mutation (1007fs) of CARD15 is impaired. The aim of this study was to investigate whether the presence of CARD15 1007fs affects activation of CD patients' own cells. Patients (4 homozygotes, 6 heterozygotes, and 6 wild-type) were matched according to clinical picture and medication. METHODS: Immune inflammatory status was evaluated by measuring monocyte HLA-DR and CD11b densities and the proportion of CD14dimCD16+ monocytes, and was found to be comparable in the three groups. Blood mononuclear cells were cultured overnight in serum-free medium alone, or the medium supplemented with LPS (0.1-10.0 ng/mL), a combination of IFN-gamma (100 IU/mL) and granulocyte-macrophage colony stimulating factor (GM-CSF) (5 ng/mL), or both. TNF and IL-10 levels in the culture supernatant were determined. RESULTS: LPS 0.1 or 1.0 ng/mL alone did not increase TNF levels. IFN-gamma/GM-CSF induced TNF release, and co-culture with LPS 1.0 or 10.0 ng/mL was strongly synergistic. CARD15 1007fs mutation was linked in a gene-dose-dependent manner to low TNF release induced by IFN-gamma/GM-CSF (P value for linear trend = 0.001). The degree of synergism in co-culture was normal or high, suggesting that 1007fs did not depress responses to LPS. IL-10 levels were not related to CARD15 1007fs. CONCLUSIONS: In CD patients, CARD15 1007fs is associated in a gene-dose-dependent manner to low mononuclear cell TNF release by IFN-gamma/GM-CSF but does not impair TNF release by LPS. This type of immune dysregulation may influence susceptibility to and/or phenotype of CD.}, address = {Depts of Surgery, Gastroenterology and Medicine, Helsinki University Hospital, Helsinki, Finland. leena.halme@hus.fi}, author = {Halme, L. and Turunen, U. and Paavola-Sakki, P. and Heli\"{o}, T. and Lappalainen, M. and F\"{a}rkkil\"{a}, M. and Kontula, K. and Repo, H.}, citeulike-article-id = {117195}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/15743002}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=15743002}, issn = {0036-5521}, journal = {Scand J Gastroenterol}, keywords = {crohn-disease}, month = {December}, number = {12}, pages = {1243--1249}, posted-at = {2005-03-08 10:50:52}, priority = {2}, title = {CARD15 frameshift mutation in patients with CROHN disease is associated with immune dysregulation.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/15743002}, volume = {39}, year = {2004} }

TY - JOUR ID - citeulike:117195 L3 - citeulike-article-id:117195 N2 - BACKGROUND: Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD). CARD15 is an intracellular receptor for bacterial lipopolysaccharides (LPS). LPS-induced activation of transfectants containing the frameshift mutation (1007fs) of CARD15 is impaired. The aim of this study was to investigate whether the presence of CARD15 1007fs affects activation of CD patients' own cells. Patients (4 homozygotes, 6 heterozygotes, and 6 wild-type) were matched according to clinical picture and medication. METHODS: Immune inflammatory status was evaluated by measuring monocyte HLA-DR and CD11b densities and the proportion of CD14dimCD16+ monocytes, and was found to be comparable in the three groups. Blood mononuclear cells were cultured overnight in serum-free medium alone, or the medium supplemented with LPS (0.1-10.0 ng/mL), a combination of IFN-gamma (100 IU/mL) and granulocyte-macrophage colony stimulating factor (GM-CSF) (5 ng/mL), or both. TNF and IL-10 levels in the culture supernatant were determined. RESULTS: LPS 0.1 or 1.0 ng/mL alone did not increase TNF levels. IFN-gamma/GM-CSF induced TNF release, and co-culture with LPS 1.0 or 10.0 ng/mL was strongly synergistic. CARD15 1007fs mutation was linked in a gene-dose-dependent manner to low TNF release induced by IFN-gamma/GM-CSF (P value for linear trend = 0.001). The degree of synergism in co-culture was normal or high, suggesting that 1007fs did not depress responses to LPS. IL-10 levels were not related to CARD15 1007fs. CONCLUSIONS: In CD patients, CARD15 1007fs is associated in a gene-dose-dependent manner to low mononuclear cell TNF release by IFN-gamma/GM-CSF but does not impair TNF release by LPS. This type of immune dysregulation may influence susceptibility to and/or phenotype of CD. IS - 12 JF - Scand J Gastroenterol SN - 0036-5521 AD - Depts of Surgery, Gastroenterology and Medicine, Helsinki University Hospital, Helsinki, Finland. leena.halme@hus.fi EP - 1249 TI - CARD15 frameshift mutation in patients with CROHN disease is associated with immune dysregulation. VL - 39 SP - 1243 KW - crohn-disease AU - Halme, L AU - Turunen, U AU - Paavola-Sakki, P AU - Heliö, T AU - Lappalainen, M AU - Färkkilä, M AU - Kontula, K AU - Repo, H PY - 2004/12// UR - http://view.ncbi.nlm.nih.gov/pubmed/15743002 ER -