Crohn's disease, a condition characterized by widespread inflammation in the gut, may arise from a weakened immune response, according to new research from the University of Toronto's Temerty Faculty of Medicine.
For the study, researchers led by Dana Philpott, a professor of immunology and laboratory medicine and pathobiology, tracked the activity of immune cells called T cells during viral infection in animal models with and without a working NOD2 gene - variations in which are strongly linked to the development of Crohn's disease.
The researchers found that fewer T cells were recruited to lymph nodes in the gut in the absence of NOD2, and these cells were less capable of fighting off subsequent infections.
The findings, published in Nature Immunology , challenge our understanding of Crohn's, a type of inflammatory bowel disease, and provide a new theory for how it starts.
"A lot of what we know about Crohn's has focused on inflammation, which I think is likely a downstream effect of the disease," said Philpott, senior author of the study, which also included Professors Jennifer Gommerman and Stephen Girardin. "As a consequence of our work, we believe we have uncovered hints as to what happens before you get pathological inflammation."
Philpott's lab has conducted several studies on 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 linked to 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 T cells, which play a central role in coordinating the body's defense against pathogens.
To investigate this question, Boyan Tsankov, a postdoctoral fellow and former PhD student in Philpott's lab, devised an innovative model to track T cell activity during infection. The results were confirmed using a more physiologically relevant model of Listeria bacterial infection, which mimics commonly seen foodborne illnesses.
Philpott said 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," said Philpott.
Tsankov noted 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 - 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," Tsankov said.
"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."
Tsankov added this 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."
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.
For Tsankov, a key takeaway from the 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.
