Researchers identify an early immune defect that may set Crohn's disease in motion

A new study by University of Toronto researchers is challenging our understanding of Crohn’s disease and providing a new theory for how it starts.

The findings suggest that the condition, which is characterized by widespread inflammation in the gut, may actually arise from a weakened immune response.

“A lot of what we know about Crohn’s has focused on inflammation, which I think is likely a downstream effect of the disease,” says Dana Philpott, a professor of immunology and laboratory medicine and pathobiology at U of T’s Temerty Medicine.

“As a consequence of our work, we believe we have uncovered hints as to what happens before you get pathological inflammation.”

Philpott is senior author of the study, published recently in Nature Immunology, that also included Temerty Medicine professors Jen Gommerman and Stephen Girardin.

Her lab studies a protein called NOD2, which functions in the immune system as a receptor that recognizes fragments of the bacterial cell wall. NOD2 receptors sit within the cell and coordinate the host’s response to infection.

Specific variations in the NOD2 gene are the strongest genetic link to the development of Crohn’s disease, a type of inflammatory bowel disease. People with these NOD2 variants are known to have an increased risk of Crohn’s disease, which prompted the researchers to ask how defects in NOD2 affect immune cells in the gut. They were specifically interested in a type of immune cells called T cells that play a central role in coordinating the body’s defense against pathogens.

To investigate this question, Boyan Tsankov, a former PhD student and now postdoctoral fellow in the Philpott lab, devised an innovative model to track T cell activity during viral infection in mice with and without a working NOD2 gene.

The researchers found that in the absence of NOD2, fewer T cells were recruited to lymph nodes in the gut and that these cells were less capable of fighting off subsequent infections by the same virus. They further confirmed these results using a more physiologically relevant model of Listeria bacterial infection, which mimics commonly seen foodborne illnesses.

Philpott says the findings were surprising because a hallmark of Crohn’s disease is an overactive T cell response and an accumulation of these immune cells in the gut.

“This was proof that NOD2 is affecting T cell recruitment and that was really novel and unexpected,” she says.

According to Tsankov, defects in NOD2 are known to cause the intestinal barrier to become more permeable, allowing more microbes to enter the system. He and Philpott think that this increased permeability combined with a weak T cell immune response are what drives the initial development of Crohn’s disease in people with NOD2 mutations.

“The intestine is full of trillions of different microbes, and we think that when you have a person with NOD2 deficiency, what may actually be initiating Crohn’s disease is an inability to clear small infections that occur within the intestine,” says Tsankov.

“Because the body is not able to control the infection, now all of a sudden it starts going into overdrive and recruiting more and more immune cells which cause inflammation and Crohn’s disease.”

He notes that their hypothesis could explain why current medications for Crohn’s disease — which primarily work by blocking immune cell recruitment and dialing down inflammation — are only effective for a subset of people with the condition.

“It could be that those people already have a dampened immune response, like people with NOD2 mutations, so those drugs won’t work because the source of inflammation is a little different,” he says.

Building on this work, one of the current projects in Philpott’s lab is testing a strategy to compensate for reduced NOD2 function as a way to restore immune balance to the gut.

Tsankov says that one of the key lessons he took away from this research is the importance of challenging dogma in the field.

“Just because a disease is associated with increased amounts of inflammation doesn’t mean that it started off that way. The nature of inflammation can be very context dependent.”

This research was funded by a Pathway Grant from the Temerty Faculty of Medicine, the Canadian Association of Gastroenterology and the TRIANGLE Program.