Researchers from the University of Oxford, Newcastle University and Cambridge University Hospitals NHS Foundation Trust have identified a previously unexplained cause of inflammatory bowel disease (IBD). In a study of more than 4,900 patients, they found that some people produce antibodies that block interleukin-10 (IL-10), a protein that normally helps control inflammation. The finding suggests that IBD includes several biologically distinct conditions and could support more targeted diagnosis and treatment.
Antibodies may disable a key anti-inflammatory protein
IBD includes Crohn’s disease and ulcerative colitis. These chronic conditions affect around 500,000 people in the UK and millions more worldwide.
Symptoms often begin during adolescence or early adulthood, and patients may face lifelong medical challenges. Treatment can involve repeated hospital visits, drugs that suppress immune activity and, in some cases, surgery. Although therapies are improving, many people need to try several treatments before finding lasting relief, creating a substantial burden for patients and significant costs for healthcare systems.
In research published in the New England Journal of Medicine, scientists found that approximately 3.5% of patients with IBD had elevated levels of antibodies that neutralize IL-10. The antibodies were found in people with both Crohn’s disease and ulcerative colitis, but not in healthy participants.
Based on the prevalence of IBD in the UK, the researchers estimate that between 15,000 and 20,000 patients nationwide may carry these harmful antibodies.
IL-10 normally acts as a chemical messenger between cells, helping the immune system limit inflammation. When antibodies block the protein, they effectively disable one of the body’s defenses against excessive immune activity. As a result, inflammation can persist and become difficult to control.
A genetic risk factor explained
The study also found a strong association between IL-10-blocking antibodies and a genetic variation known as HLA-DRB1*01:03.
Scientists at the University of Oxford first linked this genetic variation to severe IBD 30 years ago. Until now, however, the biological processes connecting the genetic risk factor with patients’ symptoms had remained unclear.
The new findings suggest that people who carry HLA-DRB1*01:03 are significantly more likely to produce antibodies that interfere with IL-10. This provides a possible explanation for how the genetic variation contributes to severe intestinal inflammation.
Professor Holm Uhrig, a pediatric gastroenterologist and director of the Center for Human Genetics at Oxford University’s Nuffield School of Medicine, was the study’s senior author.
“For decades, we have suspected an important role for interleukin-10 in patients with inflammatory bowel disease. This study provides clear evidence and contributes to the missing link between a well-known genetic mutation previously associated with severe inflammatory bowel disease and the more recently discovered autoimmunity to interleukin-10.”
“Understanding what causes inflammation provides a clear explanation for this group of diseases and opens the door to new treatments that target the autoantibodies themselves or the cells that produce them.”
Rare genetic diseases provided an important clue
The discovery builds on more than a decade of research into a rare genetic disease that disrupts the body’s ability to control inflammation.
Sophie Hambleton, professor of paediatrics and immunology at the University of Newcastle, said that studying unusual symptoms can reveal mechanisms that also contribute to more common forms of IBD.
“This discovery shows how research into rare genetic diseases can shed new light on common symptoms. The foundation was laid more than a decade ago when a genetic defect in IL-10 or its receptor was discovered in young children with severe IBD. We then found that neutralizing autoantibodies against IL-10 mimic this effect in two girls with colitis.”
Those early observations suggested that antibodies blocking IL-10 could produce effects similar to genetic defects involving IL-10 or its receptor. The latest study indicates that this mechanism also affects a larger group of patients with IBD.
Blood tests could support more targeted treatment
The results could eventually help doctors identify patients whose disease is associated with IL-10-blocking antibodies. The researchers say the findings provide a basis for developing a blood test that could detect these antibodies and help clinicians recognize affected patients earlier.
Such testing could also support treatments aimed at the underlying immune dysfunction rather than relying primarily on symptoms to guide medical decisions.
Dr Rainer Doffinger, a clinical immunologist at Cambridge University Hospitals NHS Foundation Trust, said earlier identification and targeted treatment could benefit both patients and the healthcare system.
“By identifying patients early and providing targeted treatment, we can reduce reliance on expensive ongoing treatments and prevent complications. Even small reductions in biological treatments, hospital admissions and surgeries can lead to millions of pounds a year in savings for the NHS, while also delivering significant benefits for patients through reduced interventions, improved quality of life and even durable remission.”
Potential treatments could target the antibodies themselves or the immune cells that produce them. For this particular group of patients, such approaches may reduce the need for repeated treatments, hospitalizations and surgeries, while improving the chances of lasting disease control.
Professor Simon Travis, Professor of Clinical Gastroenterology at the University of Oxford and the Kennedy Institute of Rheumatology, emphasized the importance of identifying the biological cause of inflammation in individual patients.
“This is the most exciting discovery of our lifetime specific to IBD. It means we can identify a group of people that are known to cause this disease, creating a real opportunity to change the way this disease is managed.”
The findings represent a step toward personalized treatment for IBD. In the future, biological tests could help physicians determine what is driving inflammation in individual patients and select treatments accordingly.
The study involved researchers from the Nuffield School of Medicine at the University of Oxford, the Translational and Clinical Research Institute at the University of Newcastle, and the Department of Immunology, Cambridge University Hospitals NHS Foundation Trust.
Funding was provided through the National Institute for Health and Care Research (NIHR) Biomedical Research Centers in Oxford, Cambridge and Newcastle.
Source: www.sciencedaily.com
