The Role of Human Defensins in Gastrointestinal Diseases

Jost Langhorst; Kyung-Eun Choi

Disclosures

Expert Rev Clin Immunol. 2011;7(6):779-787. 

In This Article

Immune Response in the Gut: Role of Innate Immunity for Gastrointestinal Diseases

In determining innate immune responses to bacteria in the gut, α- and β-defensins, especially HBD-2 and -3, play a crucial role.[5,28] With varying expression profiles along the intestinal tract the density of colonizing microbes is influenced with different implications on the physiology between the large and the small intestine.[3,4,8] The importance of Paneth cell defensins for IBD has been extensively demonstrated in various studies with different cohorts, disease settings, also in rodent models.[29] Typically, PCR is used to quantify the expression of defensins in the intestinal mucosa.[30] To avoid this invasive procedure the fecal defensin level can be assessed.[9,31] Our own group used this method and provided enhanced fecal HBD-2 levels in patients with active ulcerative colitis (UC) and even IBS.[9,31]

Cumulating evidence suggests a special role for HBD-2 as marker for inflammation in IBD: for example, HDB-1 is present in the healthy colon and is not affected by the presence of inflammatory (IL-1α, TNF-α, IFN-γ) or bacterial (enteroinvasive Escherichia coli) stimuli,[32] while HBD-2 is absent from the healthy colon[32] but enhanced in the acute state of inflammation in UC.[5,28,33] In addition, bacteria such as E. coli Nissle 1917[28] or proinflammatory cytokines including IL-1β and TNF-α can upregulate HBD-2 in intestinal cell lines.[5] In children with IBD, a differential regulation of HBDs is found in the mucosa, depending both on disease type and region of the gut.[34]

There is an ongoing discussion as to whether these changes in defensin expression reflect secondary symptoms of the disturbed epithelium due to inflammatory threats[35] or if these modulations are due to certain gene variations and thus reflect an innate predisposition to the development of IBD.[3] NOD2 was the first gene claimed to be in direct connection with IBD, as a susceptibility gene for ileal Crohn's disease (CD)[36,37] across different ethnicities, and NOD2 variants may explain up to 33% of the genetic susceptibility for ileal CD.[38]NOD2 is an intracellular bacterial receptor that activates NF-κB, which in turn triggers transcription of β-defensin genes[11] and regulates many proinflammatory cytokines.[32] Its role as a central regulator of antimicrobial defense is, however, not undisputed; while this relationship was found to be relevant in the skin, in the gut single studies suggest that HBD-2 seems to be independent of NOD2 mutation status.[11,35] Furthermore, healthy individuals also carry the risk alleles and thus the mutation also occurs in unaffected individuals.[39] Methodological differences can be accounted for these conflicting results. Other genetic polymorphisms, for example concerning the human multidrug resistance 1 gene (MDR1) or the autophagy-related 16-like 1 gene (ATG16L1), have been associated with IBD, although over 30 susceptibility genes for CD[40] and 15 for UC have been identified,[41,42] the precise relationship between genotype and disease behavior or response to treatment remains only rarely clarified.[38]

Another point of note is that in CD HBD-2 induction seems to be attenuated in the inflamed tissue of CD patients.[12] Furthermore, it is not yet clear what happens in cases of an entire defensin defiency. On the basis of various studies, Wehkamp and colleagues[3] believe that a relative deficiency of defensins may play a key role in enabling bacterial adherence to the mucosa, slow invasion and secondary mucosal inflammation,[3] and that these deficiencies are connected to certain gene variations and thus may predispose individuals to develop IBD.

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