B cells are special immune cells in the body that produce antibodies. In PSC for reasons unknown, immune cells destroy the cells lining the bile ducts causing them to narrow (strictures). The researchers discovered that B cells that recognize EBV are increased in individuals with PSC, suggesting that they may play a role in bile duct inflammation. Credit: K. Toverud.

Primary sclerosing cholangitis, PSC in short, is a rare liver disease that destroys the bile ducts. It is a severe condition for which we currently have no effective treatments and often results in the patient requiring a liver transplant.

"The cause of PSC is unknown, but it has long been suspected that people who develop PSC have changes to their immune system that contribute to the development of the disease, " says Brian K. Chung, a researcher at the Norwegian PSC Research Center (NoPSC) at the University of Oslo and Oslo University Hospital.

In a new study published in Nature Medicine, the researchers have found a strong link between PSC and mononucleosis (mono).

"This is the first time we can establish a strong association between this virus infection and PSC, " says Chung, who is one of the authors of the study.

Preventing mono may reduce development of PSC

Could preventing mononucleosis reduce the probability of developing PSC? The researchers believe so.

"Our findings suggest that if we can prevent infectious mononucleosis, we may significantly reduce the likelihood of developing PSC, " Chung explains.

The results may also offer the possibility of targeting the immune response in patients with PSC against the viral infection.

"If we can target the immune response in people with PSC against the infection, we may limit the damage from severe Epstein-Barr virus infection or reinfection, " the researcher says.

Mononucleosis is caused by the Epstein-Barr virus (EBV)

Mononucleosis is caused by an infection with the virus known as the Epstein-Barr virus (EBV). The virus is a member of the herpes virus family that can remain latent in the body long after the acute infection.

"This is a very common herpesvirus that infects more than 95% of people in their lifetime, " Chung says.

Typically, the virus causes mild symptoms in those infected.

"However, EBV infection can also lead to a more severe infection known as infectious mononucleosis, " the researcher notes.

This can cause a sore throat, intense pain, high fever, body aches and swollen lymph nodes in the neck. The virus could also cause an enlarged liver and spleen. In some people, mononucleosis may linger for months.

Do people with PSC have changes in their immune system?

In this current study, the researchers wanted to determine whether patients with PSC exhibit changes in their immune system compared to individuals without PSC.

They consequently compared specific lymphocytes, namely B and T cells, in PSC patients, with healthy controls.

Both T cells and B cells are essential parts of our immune system but have slightly different roles in protecting against viruses: T cells can recognize cells in the body that are infected by viruses, while B cells produce antibodies against them.

"T cells and B cells are key immune cells because they control infections and can kill cancer cells, among other functions. However, they can also inadvertently destroy healthy tissue by mistake, including the bile ducts in patients with PSC, " Chung asserts.

Found both T cells and B cells relevant to mononucleosis

The researchers at the Norwegian PSC Research Center, together with colleagues from the University of Kiel, therefore utilized several advanced immunological methods, including a technique called "T cell receptor sequencing." This method is used to define and analyze T cells.

Since T cells retain memory of past infections, researchers can identify which T cells are activated in our immune system.

"By using this technique, we saw that patients with PSC have a significantly higher percentage of T cells recognizing EBV, compared to healthy controls, " Chung says.

The researchers also found B-cells producing antibodies against the EBV, further confirming their findings with T-cells.

"We could show that PSC patients had a greater proportion of B-cells that produced antibodies against EBV compared to healthy individuals, " Chung explains.

This suggests that the patients have previously had an infection caused by the virus. However, many of the T cells and antibodies were also directed against parts of the virus that are released when the virus is active.

People with mono are 12 times more likely to develop PSC

The final step of the researchers' investigation involved analyzing electronic health records from more than 116 million individuals.

"We found that people who developed infectious mononucleosis were 12 times more likely to develop PSC compared to those who did not have infectious mononucleosis, " Chung reveals.

"This, together with our findings on T and B cells, strongly supports an immunological link between Epstein-Barr virus infection and PSC, " he adds.

Could a vaccine against mono be a possibility?

The researcher notes that their findings align with a growing body of research showing that the EBV is a strong risk factor for various chronic diseases, such as multiple sclerosis and inflammatory bowel disease.

"Given that EBV is linked to so many bad outcomes, there has been a long-standing interest in developing a vaccine against the EBV, but none have been successful thus far, " Chung says.

Such a vaccine could be a possible treatment for people with PSC.

"It would be great to have a vaccine that ensures we have a strong immune system ready to fight the EBV at all times. And a treatment that kills EBV-infected B cells, so that there is less of the virus around to cause trouble, " Chung says.

What's next?

Researchers at the Norwegian PSC Research Center have previously identified several gene variants that increase the risk of developing PSC. The findings of this study build on these earlier genetic studies. "We see that several of the most important gene variants we have previously found are related to the immune system's recognition of the Epstein-Barr virus, " says Professor and center leader Tom Hemming Karlsen.

Moving forward, the researchers at the Norwegian PSC Research Center plan to confirm these findings and attempt to understand how the virus impacts the development of PSC.

"We believe that the EBV is most important in the very early stages of disease development in PSC. Exactly how, remains to be seen, " Karlsen says.

More information: Hesham ElAbd et al, T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis, Nature Medicine (2025). DOI: 10.1038/s41591-025-03692-w  Journal information: Nature Medicine