For a person with celiac disease, eating a bagel goes something like this: chew and enjoy, the taste of the high gluten bread becomes more and more delicious due to its forbidden nature, knowing that there will be hell to pay.
Then the bagel is broken down, separated into the digestible and the non: parts of gliadin, a protein found in gluten, remain in the gut. And that’s where things start to go wrong. Immune cells detect the presence of gliadin and panic, triggering a full-blown inflammatory response that leads to pain and intestinal damage.
Exactly how that damage occurs — and why it only affects about 1% of the population, when so many more people are genetically at risk for celiac disease or develop a milder immune response — is unclear.
But new research published in Science Immunology on Friday offers a possible explanation for how T-cell tantrums lead to intestinal lesions, and hints at a process that may play a role in other autoimmune diseases. As an autoimmune disease of the small intestine, celiac disease can cause a range of symptoms, from malabsorption of nutrients to chronic diarrhea and fatigue, brain fog, osteoporosis, and more.
The paper’s senior author, gastroenterologist Arnold Han, has been studying celiac disease for more than a decade. And he saw how researchers came to realize that CD4+ T cells alone were not enough to cause intestinal damage. Instead, the field started to take notice the involvement of intraepithelial lymphocytes, or T-IELs, a population of T cells in the gastrointestinal tract.
In celiac patients, some of these T-IELs were activated, although they do not recognize and attack gluten as other T cells do. The T-IELs have so-called ‘natural killer’ receptors, which alert them to a problem – a virus or tumor, for example – that needs to be addressed.
Models of celiac disease have mostly suggested that the original scuffle, between gliadin and tantrum-throwing CD4+ T cells, caused inflammation and that in turn activated the T-IELs to damage the gut lining. But the latest study offers a different idea. “One thing we found, a little unexpectedly, is that these IELs that express the NK receptor are really, really quickly and deliberately activated by gluten,” Han said, an assistant professor in the department of medicine and microbiology and immunology at Columbia University.
Ludvig Sollid, a leading celiac disease researcher at Oslo University Hospital in Norway, said the study provided a comprehensive characterization of various T cells involved in the disease, highlighting a question: “Whether CD4+ T regulatory cells in celiac disease still have a function in disease pathogenesis.” For him, the most interesting finding in the paper was the one about the toxic duo of natural killer receptors and T-IELs.
Han is no stranger to a bit of controversy. As a postdoctoral fellow in the lab of another celiac expert, Mark Davis of Stanford, Han suggested that several types of T cells were activated simultaneously when a person with celiac disease consumed gluten. His data showed CD4+ cells in the blood, but also tumor-surveillance CD8+ T cells and unique gamma-delta T cells. But that model “was more or less discounted by the field,” he said, and the T cells were dismissed as normal, recirculating presences — not part of a systemic inflammatory response caused by gluten.
His new paper expands on the idea that different types of T cells are being hunted by gluten at the same time, and that they’re not just present as a result of recirculation. The data, based on small intestinal biopsies from 37 patients at various stages of the disease and 17 healthy controls, suggest that T-IEL cells shift from anti-inflammatory to pro-inflammatory and then kill intestinal tissue. “That part was actually quite surprising,” Han said.
As he describes it, a mostly friendly thumb war has been going on between celiac researchers for decades. Are T cells turned on at the same time? How important is the CD4+ response? Everyone builds on each other’s work and explores new possible explanations. In recent years, some in the field thought that tumor-fighting CD8+ T cells are entering suppress the disease-causing immune response of CD4+ cells. But Han’s data strongly argues against that, pointing instead to CD8+ cells as a destructive force. “It kind of goes against these other very provocative models that are being proposed,” he said. “This is something that has to be solved per field. And we do point out that the models are not mutually exclusive.”
The mechanism of how the immune system is activated by gluten — and how it leads to the kind of gut damage that seriously affects some people’s lives — matters because it could point the way to a treatment. “We know that these poor, likely tissue-damaging populations are present in patients with potential celiac disease who have no damage,” said Andrew Kornberg, a Ph.D. candidate who was first author on the paper. “We have some ideas about why they don’t cause tissue damage there. But those would be very good targets for a therapy to control these people throughout their lives so that they never progress to patients with actual tissue damage.”
And learning how T-cell-driven autoimmunity works in celiac disease, where gluten is a clear and controllable trigger, could provide valuable insights into how other autoimmune diseases occur, Han said.
There is no shortage of follow-up questions to explore: How exactly are all these immune cells activated by CD4+? And what purpose do these T cells serve in normal biology? How are they co-opted to attack healthy tissue? Given the number of people with potential celiac disease and no intestinal lesions, Kornberg suspects there’s a “last little boost” prompting the T-IELs to destroy intestinal tissue. But more research will be needed to find out exactly what that final push is.
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