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
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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