Scientists have identified abnormal immune cells that drive ongoing intestinal inflammation in coeliac patients. It’s hoped the discovery could lead to new ways to diagnose and treat the most severe form of the disease.
Mutated immune cells could be the key to why some people with coeliac disease continue to suffer debilitating symptoms despite sticking to a strict gluten-free diet.
Researchers at the and ̽ϵ Sydney discovered that certain immune cells in the gut of these patients carry genetic mutations which drive ongoing intestinal inflammation, causing symptoms like diarrhoea, pain and malnutrition.
Their research, published in , could help with earlier detection and more targeted treatment for those at risk of this most severe form of the autoimmune disorder, known as refractory coeliac disease (RCD), where symptoms persist despite dietary changes.
“It is a challenging autoimmune disorder to diagnose and treat,” said co-senior study author Professor Fabio Luciani, a visiting fellow at Garvan and Professor in Systems Immunology with ̽ϵ’s School of Biomedical Sciences.
“Refractory coeliac disease can often leave patients with pain, poor quality of life, and limited treatment options,” he said. “Now, thanks to single-cell sequencing techniques, which allowed us to analyse thousands of individual cells from intestinal biopsies, we’ve discovered this link to abnormal immune cells, which could help us develop more precise therapies for this previously unexplained condition.”
Co-senior author Professor Christopher Goodnow, Head of the Immunogenomics Lab at Garvan and a Professor with the and School of Biomedical Sciences, said doctors had struggled for decades to understand why a small proportion of coeliac patients did not improve on a gluten-free diet.
“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,” he said.
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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 with a gluten-free diet, around 1% develop RCD.
There are two types of RCD. 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.
For this study, the researchers tested biopsies taken from the small intestine of 10 individuals with RCD1 and compared them with biopsies from four people with newly diagnosed coeliac disease on a gluten-containing diet, two individuals with RCD2 and seven people without active coeliac disease.
They found the mutated – or ‘rogue’ – immune cells present in seven of the 10 people with RCD1, and in one of four people with newly diagnosed coeliac disease.
“We discovered that some patients with refractory disease have an accumulation of immune cells with genetic mutations,” said , first author of the study and a Senior Research Officer at Garvan. “These may develop during periods of chronic inflammation, such as earlier gluten exposure.
“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 were unable to determine if the mutated cells were the cause or a consequence of the chronic inflammation associated with RCD, and say further, larger studies will be needed.
Could existing drugs provide a solution?
Currently, the only treatment for RCD is broad immunosuppression, which dampens the immune system but does not specifically target 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,” said Prof. Luciani.
For example, many of the abnormal cells have mutations in the JAK-STAT pathway, which is what enables extracellular signals to be transmitted across the cell membrane to the nucleus, causing changes in DNA transcription.
“Mutations in the JAK-STAT pathway can already be 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,” said Prof. Luciani.
He is now conducting research, supported by a National Health and Medical Research Council (NHMRC) Ideas and Development Grant, to further examine the link between abnormal cells and RCD in a larger patient cohort.
Hope for those with autoimmune diseases
The research highlights the power of advanced genetic technologies in understanding autoimmune diseases, the researchers said.
“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,” said Prof. Goodnow.
"The approaches we've pioneered extend far beyond coeliac disease,” added Prof. Luciani.
“These methodologies can be applied to numerous other autoimmune conditions, accelerating our ability to develop personalised therapies for patients battling these chronic disorders."
The research was supported by John Brown Cook Foundation, Croall Foundation, The Bill and Patricia Ritchie Foundation, Miss Lyn Unsworth, a Ferris Fellowship from the Ferris Family Foundation, NHMRC Investigator Grants and the ̽ϵ Cellular Genomics Futures Institute.
