Production of pro-inflammatory cytokines by the body’s immune system triggered by a reaction to gluten in celiac patients may lead to a rare and lethal type of lymphoma, a Dutch study suggests.
The study, “CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes,” appeared in Proceedings of the National Academy of Sciences. Dr. Jeroen van Bergan, a leading cancer researcher, led the research team at Leiden University Medical Center in the Netherlands.
Celiac disease (CD) is an autoimmune disorder that results from an exacerbated inflammatory reaction to gluten in the small intestine. In patients with CD, gluten activates gluten-specific T-cells which produce pro-inflammatory cytokines that stimulate other immune cells.
Although a gluten-free diet mitigates symptoms in most patients with CD, 2 to 5 percent of those with CD don’t respond to this diet. Such patients have refractory celiac disease (RCD), which is associated with long-term inflammation and damage.
In a type of RCD – RCDII – immature white blood cells from the immune system called lymphocytes proliferate uncontrollably. Patients with a massive increase in premalignant lymphocytes in the small intestine are at high risk of developing an incurable, rare, and aggressive type of lymphoma called enteropathy-associated T-cell lymphoma (EATL).
“The immune system is seen as an ally in the battle against cancer, but that isn’t always the case,” van Bergen said in a press release.
While the pro-inflammatory cytokine interleukin (IL)-15 induces proliferation of lymphocytes, the study showed that three other pro-inflammatory cytokines – tumor necrosis factor, IL-2, and IL-21, produced by gluten-specific T-cells — were just as effective in inducing multiplication of lymphocytes obtained from biopsy samples of the duodenum of CD and RCDII patients.
The results highlight a potential mechanism by which gluten leads to exacerbated inflammation and EATL. The researchers plan to study at which stages of disease development the cytokines are involved.
“It is likely that at the time of lymphoma diagnosis, the patient has already experienced inflammation and, ultimately, to decades of intestinal inflammation,” said van Bergen. “We need to determine the extent to which it would actually help to block these newly discovered growth factors with targeted drugs at the time of diagnosis.”
Ultimately, these findings may help to develop therapies for a currently incurable disease.
“This is another great example of the importance of early-stage, discovery research,” said Lara Bennett, science communications manager at Worldwide Cancer Research, a Scottish charity. “This is a rare type of cancer but the findings could be of real benefit to this small but important group of patients with refractory CD.”
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