Inflammatory bowel disease (IBD) is a painful condition affecting the digestive system. Scientists have spent decades trying to understand its underlying causes in order to improve treatments for these chronic and often debilitating disorders.
A recent study now marks a major breakthrough. Researchers from the UK and Denmark have resolved a 30-year-old question: why is the gene variant HLA-DRB1*01:03 linked to IBD?
Linking HLA-DRB1 to IBD
Previous studies had shown that this version of the HLA-DRB1 gene appears more frequently in people with IBD, especially those with severe forms of the disease. However, scientists did not understand how this genetic variation actually contributes to the development of IBD.
We now have an explanation: people with IBD who carry the HLA-DRB1*01:03 variant are more likely to generate antibodies that wrongly target interleukin 10 (IL-10), a key signaling molecule that normally helps regulate and reduce inflammation.
As with the HLA-DRB1*01:03 variant, earlier research had also linked mutations in genes responsible for IL-10 production to IBD, but this new study helps connect those findings.
“We’ve suspected for decades that interleukin 10 plays a key role in inflammatory bowel disease,” says pediatric gastroenterologist Holm Uhlig of the University of Oxford.
“This work now offers clear evidence and fills in the missing link between a well-known genetic variant previously associated with severe IBD and the recently identified autoimmune response against interleukin 10.”
Blood Tests Reveal a Key Immune Signature in IBD
To investigate the mystery, the researchers analyzed blood samples from about 4,900 people with IBD and around 1,000 without the condition, searching for antibodies capable of neutralizing IL-10.
Researchers found these antibodies in about 3.5% of people with IBD, while none were detected in healthy individuals.
Breaking the results down further, around 2.5% of patients with Crohn’s disease and 4.4% of those with ulcerative colitis—the two main forms of IBD—had these IL-10–neutralizing antibodies in their blood.
This pattern suggests that, in a significant subset of patients, IBD may be driven by antibodies that disable IL-10, a molecule that normally acts as a brake on inflammation.
The team then compared the genetics of patients with and without IL-10 antibodies, identifying a strong link with the HLA-DRB1*01:03 variant, which was highly associated with this antibody-producing subgroup.
A Breakthrough Decades in the Making
“This is the most exciting discovery of my career in IBD,” says clinical gastroenterologist Simon Travis of the University of Oxford.
“It means we can now pinpoint a group of patients for whom we understand the cause of the disease, which opens up real opportunities to improve how we treat and manage it.”
IBD affects millions of people around the world, and its prevalence continues to rise.
Even if these findings apply to only a small fraction of patients, that still represents a substantial number of people globally.
Importantly, the researchers built their evidence by studying relatively rare and severe forms of IBD, first linking them to genetic defects in IL-10 or its receptor and later identifying the presence of neutralizing antibodies.
“This finding demonstrates how investigating rare inherited diseases can provide new insights into more common conditions,” says immunologist Sophie Hambleton of Newcastle University in the UK.
Different Forms of IBD May Have Different Causes
Like many complex diseases, IBD can appear in a wide variety of forms. This research expands current understanding of the condition, suggesting that it may have multiple underlying causes depending on the subtype.
Earlier studies have already pointed to the involvement of overactive, misdirected immune cells driving inflammation in ulcerative colitis.
Other research has shown that certain genetic variants in Crohn’s disease can strip immune cells of their normal protective functions, in a way that echoes the findings of this study.
Recognizing these differences may help pave the way for more targeted and effective treatments.
At present, doctors treat IBD with medications that help control symptoms, and they may recommend surgery in more severe cases. However, none of these options provide a true cure, highlighting the urgent need for new therapies.
“By identifying patients early and offering targeted treatments, we could reduce dependence on costly long-term therapy and help prevent complications,” says clinical immunologist Rainer Doffinger of Cambridge University Hospital.
Read the original article on: Sciencealert
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