Tom Hemming Karlsen M.D. PhD.
University of Oslo

The cause of primary sclerosing cholangitis (PSC) is unknown, yet multiple studies have implicated different human leukocyte antigen (HLA) genetic variants in disease development. Other studies have shown alterations in T cell responses of people with PSC. We aimed for an integrated analyses of adaptive immune responses in PSC by comprehensive profiling of the blood T cell repertoire of 504 individuals with PSC and 904 healthy controls along with profiling of the functional antibody repertoire of 120 individuals with PSC and 202 matching healthy controls using phage-immunoprecipitation sequencing (PhIP-Seq). In follow up to the molecular data, we queried the health care records of individuals in the TriNetX database for disease associations.
Results: Using a hypothesis-free statistical analysis framework, we identified 1,008 T cell clonotypes that were associated with PSC. These clonotypes were mostly restricted to PSC-risk HLA variants such as the HLA-B*08:01-HLA-DRB1*03:01 haplotype as well as HLA-DRB1*13:01 and were shown to target different Epstein-Barr virus (EBV) epitopes, particularly, lytic-phase antigens such as BZLF1. Furthermore, for the PhIP-Seq data we detected elevated antibody responses toward different EBV lytic-phase antigens, predominantly the BMRF1 protein. In the TriNetX database, we detected a robust association between infectious mononucleosis, which is mainly caused by EBV, and PSC (odds ratio [OR]=8.46; 95% CI: 4.53-15.80).
Conclusion: We report for the first time that in PSC there are expanded T and B cell responses against EBV. Furthermore, these responses were predominantly detected for lytic-phase antigens which may indicate that EBV-reactivation is a central theme in the pathogenesis of PSC. Whilst similar findings have been reported for multiple sclerosis, the OR for the association between PSC and infectious mononucleosis was more than 4-fold higher than that found for multiple sclerosis.