Researchers at the Garvan Institute of Medical Research and UNSW Sydney have discovered why some people with coeliac disease continue to suffer debilitating symptoms despite strictly avoiding gluten.
The study, published in Science Translational Medicine , used cutting-edge single-cell sequencing techniques to reveal that certain immune cells in the gut of these patients carry genetic mutations. The team's findings suggest these abnormal immune cells are driving ongoing intestinal inflammation that causes symptoms like diarrhoea, pain and malnutrition – pointing to a new way to diagnose and potentially treat the most severe form of coeliac disease.
"For decades, doctors have struggled to understand why a small proportion of coeliac patients do not improve on a strict gluten-free diet," says Professor Chris Goodnow, senior author of the study and Head of the Immunogenomics Lab at Garvan. "Our research suggests that, in some cases, the disease may be fuelled by immune cells that have acquired genetic mutations – something we've never been able to see before."
Rogue immune cells emerge as hidden culprits
Coeliac disease is a chronic autoimmune condition where the body mistakenly attacks the small intestine in response to gluten, a protein found in wheat, barley and rye. While most people with the condition experience relief when they remove gluten from their diet, around 1% develop refractory coeliac disease, which is where symptoms persist despite strict dietary control.
Refractory coeliac disease is classified into two types. Type 2 is caused by abnormal immune cells that can rapidly develop into an aggressive lymphoma, but the cause of type 1 has remained a mystery – until now.
"This is the first time we've been able to pinpoint a molecular signature for type 1 refractory coeliac disease," says Dr Manu Singh, first author of the study and Senior Research Officer at Garvan. "We discovered that some patients with refractory disease have an accumulation of immune cells with genetic mutations, which may develop during periods of chronic inflammation, such as earlier gluten exposure. What's interesting is that these mutations share similarities with those we see in certain lymphomas – appearing to give the cells a growth and survival advantage. This is a potential explanation for why they persist even after a patient eliminates gluten from their diet."
The researchers found that these mutated – or 'rogue' – immune cells were present in seven out of 10 patients with type 1 refractory coeliac disease. This discovery could lead to new ways to identify at-risk patients earlier and more targeted treatments.
Could existing drugs provide a solution?
Currently, the only treatment for refractory coeliac disease is broad immunosuppression, which dampens the immune system but does not specifically target the mutated cells. The researchers say their findings open the door to more precise therapies.
"If we can confirm that these mutated immune cells are driving the disease, then we may be able to target them with existing drugs," says Professor Fabio Luciani, co-senior author of the study, Visiting Scientist at Garvan and Professor in Systems Immunology at UNSW Sydney. "For example, we found that many of these aberrant cells have mutations in the JAK-STAT pathway, which is already targeted by approved drugs known as JAK inhibitors. With more investigation, this could lead to a personalised medicine approach where we treat patients based on their specific immune cell mutations."
"Understanding these mutated immune cells gives us a new way to think about why some patients don't recover on a gluten-free diet, and could help us identify which patients might benefit from different treatment approaches," adds Associate Professor Jason Tye-Din, a coeliac disease specialist at WEHI who collaborated on the study.
"The findings highlight the power of advanced genetic technologies in understanding autoimmune diseases. Until recently, these abnormal immune cells were undetectable using traditional methods, but new single-cell sequencing techniques have made it possible to analyse thousands of individual cells from intestinal biopsies," says Dr Singh.
"This research is a great example of how new genomic technologies can uncover hidden disease mechanisms. By applying these state-of-the-art tools to coeliac disease, we are beginning to solve long-standing medical puzzles and move towards more precise treatments," says Professor Goodnow.
