A new study may solve the mystery surrounding Crohn’s disease, a type of inflammatory bowel disease. This image represents an intestine affected by 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. is a common infection that causes vomiting and diarrhea. It is also one of several viruses and bacteria thought to cause disease development in people with Crohn’s disease, although the reason for this is unknown in the field.
Norovirus is a highly contagious virus that causes vomiting and diarrhea. Anyone can get norovirus and become sick, and outbreaks are common. Norovirus disease is sometimes called “food poisoning”, “gastroenteritis”, “gastroenteritis”, etc. Norovirus is the leading cause of food poisoning, but other bacteria and chemicals can also cause food poisoning.
One clue emerged when previous studies found that certain genetic alterations (mutations) are present in most people. This genetic mutation makes the intestinal lining cells more susceptible to damage. 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 in the journal on October 5, 2022 Naturea new study in mouse and human tissues shows that in healthy individuals, immune defenders called T cells secrete a protein called inhibitor of apoptosis 5 (API5), which tells the immune system to stop attacking gut lining cells. This protein adds an extra layer of protection against immune damage, allowing people with the mutation to have a healthy gut. , also found that norovirus infection inhibited T-cell secretion of API5 in mice bred to be infected with rodent Crohn’s disease, killing intestinal lining cells in the process.
The findings, led by scientists at the NYU Grossman School of Medicine, show that API5 protects most people with mutations from disease until a second trigger, such as norovirus infection, pushes some people past the disease threshold. I support the theory that
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 hypothesis that the protein protects intestinal cells, say the study authors. In human tissue, the researchers found that a Crohn’s patient’s intestinal tissue had five to ten times fewer API5-producing T cells in her than in a patient without the disease.
“Our findings help explain why the genetic association with Crohn’s disease is much broader than the actual number of patients.” Shohei Koide, PhD
“Our findings provide new insight into the critical role of the apoptosis inhibitor 5 in Crohn’s disease,” said Yu Matsuzawa-Ishimoto, M.D., Ph.D., a gastroenterologist and lead author of the study. I’m here. “This molecule may provide a new target for treating this chronic autoimmune disease that has proven difficult to manage long-term.”
Ishimoto Matsuzawa, Ph.D., a postdoctoral fellow at NYU Langone Health, said current treatments work by suppressing the immune system, putting patients at higher risk of infection and often becoming less effective after several years of use. I have. 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 “miniguts” and found that this treatment protected the gut lining cells.
“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. Dr. Ken H. Cadwell
“Our findings help explain why the genetic association with Crohn’s disease is much broader than the actual number of patients,” said Koide, co-lead author and biochemist on the study. Dr. Shohei said. Dr. Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the NYU He Perlmutter Cancer Center in 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 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.
Next, the research team plans to investigate the long-term effects of API5 injections to better understand whether Crohn’s disease, which can recur repeatedly over an extended period of time, can be effectively managed. .
Ref: “The γδ IEL Effector API5 Masks Genetic Susceptibility to Paneth Cell Death” Yu Matsuzawa, Akimin Yao, Akiko Koide, Beatrix M. Ueberheide, Jordan E. Axelrad, Bernardo S. Reis, Roham Parsa, Jessica A. Neil, Joseph C. Devlin, Eugene Rudensky, M. Zahidunnabi Dewan, Michael Cammer, Richard S. Blumberg, Yi Ding, Kelly V. Ruggles, Daniel Mucida, Shohei Koide, Ken Cadwell, October 5, 2022, Nature.
DOI: 10.1038/s41586-022-05259-y
In addition to Dr. Ishimoto Matsuzawa, Dr. Koide, and Dr. Cadwell, the other NYU Langone researcher involved in this study was Dr. Xiamin Yao. Akiko Koide, PhD; Beatrix M. Ueberheide, PhD. Jordan E. Axelrad, MD, MPH. Dr. Jessica Neal. Dr. Joseph Devlin. Eugene Rudensky, PhD. Dr. M. The Hidden Navi Dewan. Dr. Michael Camer. Kelly V. Ruggles, Ph.D. and Dr. Daniel Msida. Other investigators were Dr. Bernardo Reiss and Dr. Roham Partha of Rockefeller University in New York City. His Richard Blumberg, PhD, at Harvard Medical School in Boston. Dr. Yi Ding of his Geisinger Health in Danville, Pennsylvania.
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.
