A new study may have solved a mystery surrounding Crohn’s disease, an inflammatory bowel disease in which immune defenses meant to attack invading microbes mistakenly target the body’s own digestive tract.
The norovirusa common infection that causes vomiting and diarrhea, is one of several viruses and bacteria thought to trigger the onset of the disease in Crohn’s patients, but why is not yet known.
The clue emerged when earlier studies found that a certain genetic mutation is present in the majority of patients with the condition. This mutation makes the cells of the intestinal lining more vulnerable to damage. However, the mystery deepened again when it was learned that half of all Americans have this same genetic mutation that confers risk, but less than half a million develop the pathology.
This new work in mice and human tissue, published in the journal Nature, revealed for the first time that in healthy individuals, immune defenders called T cells secrete a protein called apoptosis inhibitor five (API5), which sends signals to the immune system. immune system to stop the attack on the cells of the intestinal lining. This protein adds an extra layer of protection against immune damage, so even those with the mutation can have a healthy gut. However, the researchers also found that norovirus infection blocks API5 secretion by T cells in mice bred to have a rodent form of Crohn’s disease, killing the cells of the intestinal lining in the process.
Led by researchers at NYU Grossman School of Medicine, the work supports the theory that API5 protects most people with the mutation against disease until a second trigger, such as norovirus infection, pushes some over the threshold of disease.
In experiments focusing on mice genetically engineered to link the mutation to human Crohn’s disease, mice given an injection of API5 survived, while half of the untreated group died. This confirmed the idea that the protein protects intestinal cells, the study authors note. In human tissue, the researchers found that those with Crohn’s disease had five to 10 times fewer API5-producing T cells in their gut tissue than those without the disease.
“Our findings offer a new perspective on the key role that apoptosis inhibitor 5 plays in Crohn’s disease,” said study lead author and gastroenterologist Yu Matsuzawa-Ishimoto. “This molecule can provide a new target for treatment of this chronic autoimmune disease, which has been difficult to manage in the long term,” he adds.
Matsuzawa-Ishimoto, a postdoctoral researcher at NYU Langone Health, points out that current therapies, which work by suppressing the immune system, put patients at high risk of infection and often become less effective after a few years of use. A treatment method targeting API5, she says, could avoid those problems.
In another set of experiments, the researchers created organ-like structures from tissue harvested from humans who tested positive for the mutation. Notably, these structures were made only from intestinal lining cells. The research team then placed API5 in these “mini intestines” and found that this treatment protected the cells lining the intestine. Furthermore, adding API5-producing T cells also protected the intestinal lining.
“The results of our research help explain why genetic links to Crohn’s disease are much broader than the actual number of people with the disease,” said study co-senior author and biochemist Shohei Koide, a professor in the Department of Crohn’s disease. in Biochemistry and Molecular Pharmacology from NYU Langone and a member of its Perlmutter Cancer Center.
“Our study suggests that when norovirus infects people with a weakened ability to produce apoptosis inhibitor five, tips the scales toward full-blown autoimmune disease,” adds co-senior author and microbiologist Ken Cadwell, professor of microbiology at NYU Langone.
Cadwell cautions that while the study authors obtained the API5 protein from human rather than rodent tissue, it remains unclear whether the injection treatment can be administered safely in humans.
Now, the research team plans to explore the long-term effects of API5 injections to better understand whether prospective treatment can effectively control Crohn’s disease, which can recur repeatedly over a long period of time.