Interleukin-21 May Play Key Inflammation Role in Celiac Disease
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A team of Italian and British researchers recently evaluated the production of IL-21 in the intestinal mucosa of patients with untreated celiac disease. Several studies have documented the ability of IL-21's to regulate cytokine production by certain T cells. Another recent study demonstrated a connection between celiac disease and what is called the susceptibility locus in the chromosome 4q27, which harbors the IL-21 gene.
The researchers, led by Dr. G. Monteleone at Universita Tor Vergata in Rome, set out to examine the molecular mechanisms tying IFN-gamma with celiac disease. The team found that people with celiac disease produce excess IL-21, and that IL-21 is responsible for encouraging production of interferon-gamma (IFN-gamma).
In active celiac disease, large numbers of polarized T helper Type 1 (Th1) cells accumulate in the upper intestinal tract, where they produce large amounts of IFN-gamma. The team looked at upper bowel biopsies taken from 91 people from 22 to 54 years of age. 43 had untreated celiac disease, 12 patients had treated celiac disease, and 36 served as healthy controls. The mucosa of those with untreated celiac disease showed highly elevated IL-21 levels compared with the healthy control group (P < 0.001), while those with treated celiac disease showed the same levels of IL-21.
When the research team blocked endogenous IL-21 in ex vivo organ cultures from untreated celiac disease patients, they saw a reduced expression of both IFN-gamma and T-bet, a master regulator of Th1 cell response.
When the research team stimulated biopsy cultures with a peptic-tryptic digest of gliadin (PT) explants, the biopsies of patients with treated celiac disease showed elevated IL-21, while the controls showed no such elevation. The team was able to use an anti-IL-21 antibody to substantially reduce the enhancement of T-bet expression by PT (P = 0.01), whereas they saw no such reduction using a control antibody.
These results indicate that up-regulation of IL-21 in celiac disease depends on gluten-driven active inflammation. As such, IL-21 may have a crucial role in promoting the destructive inflammation in celiac disease. If so, neutralizing the production or presence of IL-21 might offer a promising and alternative therapeutic approach in treating celiac disease, especially in treating cases of celiac disease that are unresponsive to a gluten-free diet.
In a side note, several doctors have noted that the role of IL-21 does not seem to be exclusive to celiac disease, as the biopsies of patients with Helicobacter pylori infections, and those suffering from Crohn's disease show similar increases in IL-21 synthesis.
Gut 2008: 57; 879-881,887-892.
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