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Research team from the Cluster of Excellence PMI shows elevated immune responses toward Epstein-Barr virus in individuals with primary sclerosing cholangitis (PSC). / Publication in Nature Medicine
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that affects the bile ducts, where chronic inflammation, coupled with fibrosis lead to bile duct obstruction and ultimately liver failure. PSC has no cure, and liver transplantation is the only treatment option in advanced stages. Despite being a rare-disease 10–15% of all liver transplantations in Northern Europe and the USA can be attributed to PSC. The burden on patients and healthcare systems is significant. Additionally, 60–80 percent of people with PSC also suffer from inflammatory bowel disease. The causes of PSC remain largely unknown, though genetic predisposition and dysregulated immune responses are being discovered.
Now, researchers from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI) based in Kiel have shown that in individuals with PSC, there is an elevated immune responses toward the Epstein-Barr virus (EBV), hinting toward a potential link between EBV reactivation and disease development. Their findings have now been published in the renowned journal Nature Medicine.
Comprehensive Molecular and Statistical Analyses Reveal A Link
The research team conducted a detailed investigation of the immune system of individuals with PSC and matching healthy controls, focusing on both T cells and B cells. T cells have highly specific receptors on their surface (T cell receptors) that recognize distinct parts of pathogens presented by a group of proteins, termed, human leukocyte antigens (HLAs). The collection of unique TCRs present in a sample is referred to as the T cell repertoire.
Using modern sequencing technologies, the team analyzed blood samples from more than 500 individuals with PSC and over 900 healthy controls to identify TCRs expanded in individuals with PSC. They found that certain receptors occurred more frequently in individuals with PSC relative to healthy controls. However, the sequences alone do not reveal which pathogens these receptors recognize. To do so, the researchers compared the sequences to specialized databases that contain information from previous studies on which TCRs recognize which pathogens.
“We discovered that the collection of T cell receptors found more frequently in individuals with PSC —and thus are robustly implicated in the disease—contained multiple TCRs that bind to several proteins of the Epstein-Barr virus (EBV),” explains Dr. Hesham ElAbd, first author of the study and postdoctoral researcher at the Institute of Clinical Molecular Biology (IKMB) at Kiel University (CAU) and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel. “This suggests a possible link between the elevated immune responses toward EBV and the development of PSC,” ElAbd continues.
Connection Also Confirmed at the B Cell Level
“To ensure the robustness of our findings, we didn’t just analyze T cells but also looked at B cells,” ElAbd explains. B cells produce antibodies that circulate in the blood and, like T cells, can bind to parts of pathogens and trigger immune responses, however, without the need for a presentation by HLA proteins. The overall composition of antibodies in a person’s blood can also provide insights into prior exposure to pathogens and other microorganisms and which infections are acutely present.
The research team used a high throughput antigenic screening approach, namely, phage- immunoprecipitation sequencing (PhIP-Seq), to determine the antigenic specificity of the collection of antibodies, that is, the antibody repertoire, of individuals with PSC and matching healthy controls. This way researchers also observed a stronger immune response to several EBV antigens at the B cell level in individuals with PSC compared to healthy controls.
Epstein-Barr Virus Reactivation Occurs in PSC Patients
More than 95% of the global population is infected with EBV, for some, the initial infection causes infectious mononucleosis (glandular fever), however, for most individuals it is an asymptomatic infection. Afterward, the virus remains dormant in the body, entering what is known as the latent phase. EBV oscillates between a lytic and a latent phase, and the reemergence from a latent state toward a lytic phase state is known as EBV reactivation.
“The immune system targets different EBV proteins in the lytic phase than in the latency phase. Our analyses showed that in individuals with PSC, the virus is in a reactivated state. This reactivation appears to play a role in the development of PSC similar to what has been seen in other chronic inflammatory diseases,” ElAbd explains. Previous studies have shown that EBV reactivation is also associated with other autoimmune and immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus.
The researchers also confirmed their findings by analyzing American health records from over 116 million individuals. The epidemiological data showed a link between infectious mononucleosis and the development of PSC.
“These results show a clear association between the virus and PSC, but they do not yet prove a causal relationship. Further studies are needed to investigate this,” emphasizes Professor Andre Franke, senior author of the study and Director of the IKMB. “If a causal connection exists, it will be crucial to understand how the Epstein-Barr virus influences the development of PSC,” Franke adds. “We also still don’t know why some people who carry the virus develop PSC while most do not. Other factors, such as genetics and environmental influences, must also play a role.” The research team has already found initial evidence that people who develop PSC or multiple sclerosis after EBV infection have develop mononucleosis later in life than the average person, i.e. early infection appears to be beneficial for humans.
The study was conducted in collaboration with research teams at Oslo University Hospital Rikshospitalet, Medical University of Vienna, University Hospital Basel, University of Basel and University Medical Center Hamburg-Eppendorf.
Professor Dr. Andre Franke
Institute for Clinical Molecular Biology, Kiel University und UKSH
Medical Faculty
+49 431 500 15110
a.franke@mucosa.de
ElAbd, H., Pesesky, M. et al.: T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis. Nat Med (2025). https://doi.org/10.1038/s41591-025-03692-w
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