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

L Halme1, U Turunen, P Paavola-Sakki

  • 1Depts of Surgery, Gastroenterology and Medicine, Helsinki University Hospital, Helsinki, Finland. leena.halme@hus.fi

Scandinavian Journal of Gastroenterology
|March 4, 2005
PubMed

Insights

The CARD15 1007fs mutation in Crohn disease patients is linked to reduced TNF release when stimulated by IFN-gamma/GM-CSF. This immune dysregulation may impact CD susceptibility and phenotype.

Area of Science:

  • Immunology
  • Genetics
  • Gastroenterology

Background:

  • Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD).
  • CARD15 acts as an intracellular receptor for bacterial lipopolysaccharides (LPS).
  • Previous studies indicated impaired LPS-induced activation of CARD15 with the 1007fs frameshift mutation.

Purpose of the Study:

  • To investigate if the CARD15 1007fs mutation affects the activation of immune cells in CD patients.
  • To determine the impact of CARD15 1007fs on cytokine release in response to specific immune stimuli.

Main Methods:

  • Compared immune inflammatory status (monocyte HLA-DR, CD11b, CD14dimCD16+ monocytes) in CD patients with CARD15 1007fs (homozygotes/heterozygotes) and wild-type.
  • Cultured blood mononuclear cells with LPS, IFN-gamma/GM-CSF, or both.
  • Measured TNF and IL-10 levels in culture supernatants.

Main Results:

  • IFN-gamma/GM-CSF induced TNF release, with strong synergy when combined with LPS.
  • CARD15 1007fs mutation showed a gene-dose-dependent association with lower TNF release induced by IFN-gamma/GM-CSF (P=0.001).
  • Responses to LPS stimulation were not impaired by the 1007fs mutation; IL-10 levels were not related to CARD15 1007fs.

Conclusions:

  • In CD patients, CARD15 1007fs is associated with reduced mononuclear cell TNF release upon IFN-gamma/GM-CSF stimulation.
  • The mutation does not impair TNF release induced by LPS.
  • This specific immune dysregulation may contribute to CD susceptibility and/or influence its clinical phenotype.
Abstract

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