Study may have solved a mystery surrounding Crohn's disease

Study may have solved a mystery surrounding Crohn's disease

A new study may have solved a mystery surrounding Crohn's disease, a type of inflammatory bowel disease in which the immune system is supposed to attack invading microbes rather than mistakenly attacking the body's digestive tract. Norovirus, a common infection that causes vomiting and diarrhea, is one of several viruses and bacteria thought to trigger disease outbreaks in people with Crohn's disease. However, the reason for this is not known.

A clue emerged when previous studies found that most people with the condition have a certain genetic change (mutation). This mutation makes the cells in the intestinal lining more susceptible to damage. But the mystery deepened when it was learned that half of all Americans have the same risky genetic mutation, but fewer than half a million develop Crohn's disease.

The new work on mice and human tissue, published online Oct. 5 in the journal Nature, showed for the first time that in healthy people, immune defenses called T cells secrete a protein called apoptosis inhibitor 5 (API5), which signals the immune system to stop attacking cells in the intestinal lining. This protein provides an additional layer of protection against immune damage, allowing people with the mutation to have a healthy gut. However, the researchers also found that norovirus infection blocks T cell secretion of API5 in mice bred with a rodent form of Crohn's disease, killing intestinal cells in the process.

The work, led by researchers at NYU Grossman School of Medicine, supports the theory that API5 protects most people with the mutation from the disease until a second trigger, such as a norovirus infection, pushes some over the disease threshold.

In experiments with mice genetically modified to have the mutation linked to Crohn's disease in humans, mice given an API5 injection survived, while half of the untreated group died. This confirmed the idea that the protein protects intestinal cells, say the study authors. In human tissue, researchers found that people with Crohn's disease had between 5 and 10 times fewer API5-producing T cells in their intestinal tissue than people without the disease.

Our results provide new insights into the key role played by apoptosis inhibitor 5 in Crohn's disease. This molecule may provide a new target for the treatment of this chronic autoimmune disease, which has proven difficult to treat in the long term.”

Yu Matsuzawa-Ishimoto, MD, PhD, principal investigator and gastroenterologist

Dr. Matsuzawa-Ishimoto, a postdoctoral fellow at NYU Langone Health, notes that current therapies that suppress the immune system put patients at high risk of infection and often lose effectiveness after a few years of use. He adds that a treatment that targets API5 could avert these problems.

In another series of experiments, the researchers created organ-like structures from tissue from people who tested positive for the mutation. It is noteworthy that these structures consisted only of cells from the intestinal wall. The research team then infused API5 into these “miniguts” and found that this treatment protected the cells in the intestinal lining. Furthermore, the addition of API5-producing T cells also protected the intestinal mucosa.

“The results of our study help explain why the genetic associations with Crohn's disease are much broader than the actual number of people who suffer from the disease,” says Shohei Koide, Ph.D., study co-author and biochemist. Dr. Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the Perlmutter Cancer Center at NYU Langone.

“Our study suggests that norovirus infection of individuals with a weakened ability to produce apoptosis inhibitor 5 precipitates full-blown autoimmune disease,” adds Ken H. Cadwell, PhD, co-senior author of the study and Recanati Family Microbiologist Professor of Microbiology at NYU Langone.

Dr. Cadwell points out that while the study authors obtained the API5 protein from human tissue rather than rodents, it remains unclear whether the injection treatment can be safely administered in humans.

Next, the research team plans to study the long-term effects of API5 injections to better understand whether future treatment can effectively treat Crohn's disease, which can flare up repeatedly over a long period of time.

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

Dr. Cadwell has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech and Abbvie and has served as a consultant for Puretech Health, which is developing microbiome therapies, as well as GentiBio and Synedgen. Dr. Koide has received research support from Argenx BVBA, Black Diamond Therapeutics and Puretech Health and served as a consultant for Black Diamond Therapeutics. NYU Langone has pending patents (10,722,600, 62/935,035 and 63/157,225) for therapies developed from this treatment approach, which Dr. Cadwell, Dr. Koide, Dr. Matsuzawa-Ishimoto and NYU Langone could benefit financially. The terms of these relationships will be administered in accordance with NYU Langone policies.

Source:

NYU Langone

Reference:

Matsuzawa-Ishimoto, Y., et al. (2022) The γδ-IEL effector API5 masks genetic susceptibility to Paneth cell death. Nature. doi.org/10.1038/s41586-022-05259-y.

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