Research may have solved the mystery surrounding Crohn’s disease

A new study may have solved the mystery surrounding Crohn’s disease, a type of inflammatory bowel disease in which immune defenses intended to attack invading microbes mistakenly target the body’s own digestive tract instead. Yes. Norovirus, a common infection that causes vomiting and diarrhea, is one of several viruses and bacteria thought to cause disease episodes in people with Crohn’s disease, but we don’t know why. .

One clue emerged when past research found that certain genetic alterations (mutations) were present in most people. increase. But the mystery deepens again when it turns out that while half of all Americans carry this same risk-conferring genetic mutation, fewer than half a million of them develop Crohn’s disease.

Published online October 5 in the journal Naturea new study in mouse and human tissues suggests that in healthy individuals, immune defenders T cells It secretes a protein called apoptosis inhibitor 5 (API5) that signals the immune system to stop attacking gut lining cells. This protein adds an extra layer of protection against immune damage, so even people with the mutation can have healthy guts. We also found that API5 blocked T-cell secretion in mice bred as such, killing intestinal lining cells in the process.

The study, led by researchers at the NYU Grossman School of Medicine, theorizes that API5 protects most people with the mutation from disease until a second trigger, such as norovirus infection, crosses the disease threshold. is supporting

In experiments centered on mice genetically engineered to carry mutations associated with human Crohn’s disease, API5-injected mice survived, while half of the untreated group died. This confirms the idea that the protein protects intestinal cells, the authors of the study said. Researchers have found between 10 and 10 times less.

Our findings provide new insight into the critical role played by the apoptosis inhibitor 5 in Crohn’s disease. This molecule may provide a new target for treating this chronic autoimmune disease that has proven difficult to manage long-term.”

Yu Matsuzawa-Ishimoto, MD, PhD, Study Lead Author and Gastroenterologist

Dr. Ishimoto Matsuzawa, a postdoctoral fellow at NYU Langone Health, notes that current treatments that work by suppressing the immune system leave patients at risk of infection and often become less effective after years of use. doing. Therapies targeting API5 may circumvent these problems, he adds.

In another series of experiments, researchers created organ-like structures from tissue collected from humans who tested positive for the mutation. Notably, these structures were made exclusively of intestinal lining cells. The research team then dropped API5 into these “mini-guts” and found that this treatment protected gut lining cells.

“Our findings help explain why the genetic association with Crohn’s disease is much broader than the actual number of patients,” said study co-lead author and biochemist Shohei Koide, Ph.D. says. Dr. Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the Perlmutter Cancer Center at New York University Langone.

“Our study suggests that when norovirus infects a person with a weakened ability to produce the inhibitor of apoptosis 5, the balance tilts toward a full-blown autoimmune disease,” said the study’s co-lead author. adds microbiologist Ken H. Cadwell, PhD, of the Recanati Family. Professor of Microbiology at NYU Langone.

Dr. Cadwell cautions that while the study authors extracted the API5 protein from human tissue rather than rodent tissue, it remains unclear whether infusion treatments can be safely administered to humans.

The research team next plans to investigate the long-term effects of API5 injections to better understand whether they can effectively manage Crohn’s disease, which can recur repeatedly over time.

Funding for this study was provided by National Institutes of Health grants R0IL123340, R0IDK093668, R0IAI140754, R0IAI121244, R0IAI130945, R0IDK124336, and R0IDK088199. Additional funding came from the Howard Hughes Medical Institute, the Kenneth Rainin Foundation, the Crohn’s Disease and Colitis Foundation, and the Takeda-Columbia-NYU Alliance.

Dr. Cadwell has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech, and Abbvie, and has consulted with Puretech Health, which develops microbiome therapies, and GentiBio and Synedgen. Dr. Koide has received research support from Argenx BVBA, Black Diamond Therapeutics, and Puretech Health, and has served as a consultant to Black Diamond Therapeutics. NYU Langone has patents pending (10,722,600, 62/935,035, and 63/157,225) on treatments developed from this therapeutic approach to Dr. Cadwell, Dr. Koide, Dr. Matsuzawa-Ishimoto, and Dr. NYU Langone. may be economically beneficial. The terms and conditions of these relationships are governed by NYU Langone policy.