Researchers at the University of Oxford have identified a previously unrecognized driver of inflammatory bowel disease: autoantibodies that neutralize interleukin-10, the immune system’s primary anti-inflammatory signaling molecule. The finding, published in the New England Journal of Medicine, applies to approximately one in 30 IBD patients and represents the strongest known genetic association for any autoimmune antibody response in the disease.
How they found it
The team, led by Holm Uhlig at Oxford’s Centre for Human Genetics, used a cellular IL-10 reporter assay to screen serum from nearly 5,000 IBD patients enrolled in the Oxford Gastrointestinal BioBank and the UK IBD BioResource. They found that 173 of 4,909 patients, or 3.5 percent, carried autoantibodies that bound to and neutralized IL-10. Among 1,006 healthy controls, zero carried the antibodies.
Functional validation confirmed that these autoantibodies are not passive markers. In an in vitro cytokine-release bioassay, serum with high anti-IL-10 activity suppressed detectable IL-10 and produced an exaggerated proinflammatory cytokine response, including elevated IL-23, IL-1-beta, tumor necrosis factor, and IL-6. The body’s inflammation brake had been physically removed.
The genetic link
The autoantibodies were overwhelmingly associated with the HLA-DRB1*01:03 allele. The odds ratios were extraordinary by any standard: 50.0 in the Oxford-imputed cohort, 24.7 in the UK BioResource cohort, and 29.5 by high-resolution sequencing. This is the strongest HLA association ever reported for an autoimmune antibody response in IBD.
HLA-DRB1*01:03 has historically been linked to severe ulcerative colitis often requiring major surgery. The new finding provides a mechanistic explanation: these patients carry a genetic predisposition to develop autoantibodies that disable the IL-10 signaling pathway, producing a functional phenocopy of monogenic IL-10 receptor deficiencies previously described in children with severe early-onset IBD.
Clinical significance
For the 3.5 percent of IBD patients who carry these autoantibodies, the implication is that their disease has a fundamentally different mechanism than the broader IBD population. Current treatment algorithms use a trial-and-error sequence of immunosuppressants, biologics, and surgery. For this subgroup, therapies targeting the specific autoimmune mechanism may be more appropriate.
“Autoimmune responses are not at all part of the therapeutic repertoire, and that is why we feel it is a relevant study,” Uhlig said.
Patients with the HLA-DRB1*01:03 variant could be identified by genetic testing early in the disease course. Brad Pasternak at Phoenix Children’s Hospital, who was not involved in the study, noted that identifying these patients early could allow clinicians to move toward mechanism-directed therapies more quickly rather than relying on sequential drug trials.
Potential therapeutic strategies include B-cell depletion, plasma exchange to remove circulating autoantibodies, or therapies aimed at restoring IL-10 function in affected patients.
What remains unknown
The trigger for these autoantibodies is not yet known. Uhlig called the question of why they develop “a question of intense interest.” The HLA association suggests a genetic predisposition, but environmental or infectious triggers may also be involved.
Whether therapies that restore IL-10 signaling are clinically achievable in this patient subgroup remains to be tested. An accompanying editorial by Bastard and Casanova places the finding in the broader context of anti-cytokine autoantibodies, which have previously been identified in severe COVID-19 and mycobacterial disease but are only now being recognized in autoimmune inflammatory disease.
The study also raises the question of whether similar autoantibody-driven mechanisms operate in the majority of IBD patients who do not carry the HLA-DRB1*01:03 variant. The Oxford team is actively investigating this possibility.
Source: Gharahdaghi, N., Yeh, P-J., Ceron-Gutierrez, L. et al. Interleukin-10 Autoantibodies and HLA-DRB101:03 in Inflammatory Bowel Disease. New England Journal of Medicine 394(22), 2212-2222 (2026). DOI: 10.1056/NEJMoa2513654*