Crohn's Disease may Be Caused by Disabled Immune Gut Cells

Researchers at Washington University School of Medicine in St. Louis have shown in a new study that the health of specialized gut immune cells is associated with a gene associated with Crohn's disease.
The researchers said that the link intrigued them because Crohn's disease is believed to be caused by misdirected immune responses in the intestine that damage gut tissue.

They revealed that cells in the mouse model they used for their study had altered genetic activity that could lead to increased production of certain hormones, which are elevated in some Crohn's patients.

"We now have a significant new piece of the puzzle that is Crohn's disease, but not the solution just yet," Nature magazine quoted says senior author Dr. Herbert W. "Skip" Virgin, the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology, as saying.

"As many as 30 different areas in human DNA have potential links to Crohn's disease, and to develop new treatments it's going to be essential to find out how each of them, as well as environmental factors, contribute to the disorder," Virgin added.

Studies conducted in the past have revealed that some Crohn's disease patients have a mutation in a gene known as Atg16L1.

Though the mutation increases the risk of contracting the disease, it does not automatically lead to Crohn's disease.

With a view to gaining further knowledge on this link, a postdoctoral student in Virgin's lab named Dr. Ken Cadwell studied two lines of mice with a genetic alteration that reduced their ability to make the Atg16L1 protein.

The researchers observed that decreased Atg16L1 protein had pronounced effects on Paneth cells-immune cells in the lining of a portion of the small intestine that make proteins and antimicrobial peptides that they package as granules, and secrete into the intestine to defend the body against infection.

"When they have less Atg16L1, the Paneth cells survive, but their ability to secrete granules is significantly impaired," Cadwell says.

The researchers later selected tissue from patients with mutated Atg16L1, and compared human Paneth cells to cells from their mouse model.

Virgin said that there were "striking similarities".

The researchers then conducted a follow-up experiment to learn how Atg16L1 helps the Paneth cell. They knocked out a related gene, Atg5, in mice.

Like Atg16L1, Atg5 contributes to an important process called autophagy that lets cells consume and reuse their own resources and may have other functions as well.

The team observed that Paneth cells in mice had impairments similar to the first line, suggesting that Atg16L1's contributions to the Paneth cell may be linked to autophagy.

"We don't yet know why having abnormal Paneth cells would predispose a person to Crohn's disease or to what degree other genes linked to Crohn's may affect the Paneth cell, but those are just a few of the very interesting questions to follow up on from these results," Virgin said.


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