Genetic Polymorphisms Spill Their Guts

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Science Translational Medicine  04 Jun 2014:
Vol. 6, Issue 239, pp. 239ec100
DOI: 10.1126/scitranslmed.3009418

Human beings are ecosystems; we are colonized by bacteria that are not only not harmful but are even helpful. Commensal bacteria in the gut aid in digesting food and protecting us from pathogens. However, in people with inflammatory bowel disease (IBD), the immune system does not treat commensal bacteria as friendly neighbors. Instead, an inappropriate immune response to gut bacteria may contribute to intestinal inflammation and pathogenesis in IBD. Consistent with this, polymorphisms in immune genes such as ICOSLG, as well as receptors such as NOD2 that recognize bacterial products, are commonly found in people with IBD. How these polymorphisms influence the function of the gene to confer increased disease risk remains largely unknown.

The receptor encoded by the gene ICOSLG binds to ICOS on T cells and coordinates their activation and function. However, Hedl et al. report that ICOS interactions are not just for T cell stimulation anymore. They noticed that both of these molecules were expressed on human dendritic cells (DCs) in response to stimulation with the bacterial product, muramyl dipeptide (MDP), which is the ligand for NOD2. Homotypic interactions between human DCs expressing ICOSL and ICOS induced secretion of inflammatory cytokines such as interleukin-1β (IL-1β). These cytokines are critical to preventing the unwanted bacterial growth and penetration within the intestine that is often associated with IBD. Most importantly, these investigators demonstrate that DCs isolated from patients with the ICOSLG susceptibility loci expressed lower levels of ICOSL, rendering the DCs unable to secrete IL-1β and identifying a link between a genetic polymorphism and function.

These studies offer insight into how this particular polymorphism within ICOSLG could lead to increased IBD: by crippling the immune system’s ability to control intestinal bacteria. Because these studies were performed in cultured human cells, they were unable to directly test whether these polymorphisms cause decreased bacterial killing and worsened IBD. However, future studies in animal models would bridge this gap.

IBD is a complex disease that has been linked to dozens of genes in addition to environmental factors, making a single treatment option for all IBD patients impossible. These exciting findings and more like them could lead to the development of personalized therapies for diseases such as IBD, based on the patients genetic predisposition.

M. Hedl et al., Pattern recognition receptor signaling in human dendritic cell is enhanced by ICOS ligand and modulated by the Crohn’s disease ICOSLG risk allele. Immunity 40, 734–746 (2014). [Abstract]

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