A new study from the University of Toronto has revealed that Crohn's disease, a chronic inflammatory bowel condition, may originally stem from an impaired immune system rather than an overactive one, as was previously believed.
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This discovery rewrites the scientific understanding of the disease's nature and provides a new explanation for how it develops.
The study, led by Dr. Dana Philpott and published in the journal Nature Immunology, tracked the activity of immune cells known as T cells during infection in animal models—some carrying a healthy NOD2 gene and others with a defect in this gene, mutations of which have been strongly linked to an increased risk of Crohn's disease.
Researchers found that the absence of a functional NOD2 gene leads to fewer T cells being recruited to the intestinal lymph nodes, rendering these cells less capable of fighting off infection.
This finding is surprising, as the hallmark of Crohn's disease has always been an exaggerated T cell response and their accumulation in the gut, rather than the opposite.
"Most of what we know about Crohn's disease has focused on inflammation, which I think is just a downstream effect of the disease," Philpott said. "We've discovered what happens before that inflammation arises—an initial weakness in the primary immune response."
The NOD2 gene functions in the immune system as a receptor that recognizes fragments of bacterial cell walls, helping coordinate the body's response to infection. When this gene is defective, the intestinal barrier becomes more permeable, allowing more microbes to enter the body.
Lead author Bojan Tsankov explains the new hypothesis: "The gut is home to trillions of microbes. When someone has a defect in the NOD2 gene, the body is unable to clear minor infections within the gut. This forces the immune system to overcompensate and recruit more cells, leading to the chronic inflammation we recognize as Crohn's disease."
This hypothesis offers a crucial explanation for why current Crohn's disease medications work for some patients but fail for others. Existing treatments primarily function by suppressing inflammation and preventing the recruitment of immune cells. However, if the root cause is immune impairment rather than overactivity, these drugs may prove ineffective for individuals carrying NOD2 mutations, as the underlying driver of the disease is different.
Based on these findings, Philpott's lab is currently working on developing a strategy to compensate for reduced NOD2 function, aiming to restore immune balance in the gut and treat the disease at its origin, rather than merely mitigating inflammatory symptoms.
"Just because a disease is associated with elevated levels of inflammation doesn't mean it started that way," Tsankov concluded. "The nature of inflammation is context-dependent, and this discovery serves as a reminder of the importance of challenging established ideas to gain a deeper understanding of diseases."
Medical Xpress
