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Slipping the barrier: how variants in CARD15 could alter permeability of the intestinal wall and population health
  1. S Schreiber
  1. Correspondence to:
    Professor S Schreiber
    Institute for Clinical Molecular Biology and Department for General Internal Medicine, University-Hospital-Schleswig-Holstein, Schittenhelmstr 12, 24105 Kiel, Germany; s.schreiber{at}

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The increased intestinal permeability in Crohn’s disease is associated with the presence of variants in the CARD15 gene that are regarded as causative for Crohn’s disease, suggesting a genetic rather than an environmental background for intestinal barrier dysfunction in Crohn’s disease

The association of sequence variants in the capsase recruitment domain family, member 15 (CARD15) gene that encodes for the protein nucleotide binding oligomerisation domain 2 (NOD2) with Crohn’s disease1–3 has been a major breakthrough, illustrating the importance of disturbed innate immune function in the aetiology of chronic intestinal inflammation. Three main variants (R702W, G908R, and 1007fsInsC, originally labelled as single nucleotide polymorphisms 8, 12, and 13, respectively) in addition to a large number of private rare variants4 lead to incapacitation of the resulting NOD2 protein product.5–8 However, dissection of the main threads of NOD2 induced pathophysiology has resulted in controversial hypotheses.9,10 Unravelling the complex pathophysiology induced by expression of variant NOD2 proteins has therefore become one of the new challenges of clinical research in Crohn’s disease. NOD2 is expressed in various cell types, including intestinal epithelial cells,7,8 macrophages/monocytes, and B cells.6

Intestinal epithelial cells (IECs) have long been regarded as passive components of the mechanical part of the barrier and were thought to be merely involved in innate immune defence. In recent years it has become clear that IECs express PAMP receptors and are capable of recognising invading and adherent pathogens under …

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