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Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients

Henri Braat1, Pieter Stokkers, Tijmen Hommes

  • 1Department of Experimental Internal Medicine, Academic Medical Center, P.O. Box 22700, Meibergdreef 9, 1100 DE Amsterdam, The Netherlands.

Journal of Molecular Medicine (Berlin, Germany)
|July 13, 2005
PubMed

Insights

Mutations in pattern recognition receptors, like NOD2 and TLR4, are linked to Crohn's disease (CD). These genetic variations impact gene expression in immune cells, contributing to CD development.

Area of Science:

  • Immunology
  • Genetics
  • Gastroenterology

Background:

  • Growing evidence links germ-line mutations in pattern recognition receptors (PRRs) with immune activation to increased Crohn's disease (CD) incidence.
  • The precise cellular and molecular effects of these PRR mutations remain unclear.

Purpose of the Study:

  • To investigate the prevalence of specific single nucleotide polymorphisms (SNPs) in NOD2, TLR4, and TLR5 genes within a Dutch cohort.
  • To functionally characterize the impact of NOD2 and TLR4 mutations on immune cell gene expression.

Main Methods:

  • Genotyping analysis of NOD2, TLR4, and TLR5 SNPs in 637 CD patients, 127 controls, and patients with ulcerative colitis.
  • Stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively.
  • Comparison of gene expression profiles to assess the functional consequences of identified mutations.

Main Results:

  • Specific NOD2 alleles (R702W, 1007fs) and a TLR4 allele (A299G) were significantly more common in CD patients compared to controls or ulcerative colitis patients.
  • Homozygous mutations in TLR4 and NOD2 led to distinct, yet overlapping, gene expression profiles in stimulated dendritic cells.
  • A substantial number of genes were concordantly up- or down-regulated in DCs with these mutations.

Conclusions:

  • Genetic variations in innate immunity genes, specifically NOD2 and TLR4, are associated with Crohn's disease.
  • These mutations induce similar transcriptional changes in immune cells, potentially explaining comparable clinical presentations in CD patients.
  • The findings support a model where innate immune gene mutations contribute to the genetic basis of Crohn's disease.

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