ElAbd Hesham, Pesesky Mitchell, Innocenti Gabriel, Chung Brian K, Mahdy Aya K H, Kriukova Valeriia, Kulsvehagen Laila, Strobbe Dennis, Stühler Claudia, Mayr Gabriele, May Damon H, Prinzensteiner Melanie, Steiert Tim A, Tran Florian, Hadjihannas Michel V, Günther Rainer, Rosati Elisa, Mucha Sören, Lieb Wolfgang, Ziemann Malte, Dempfle Astrid, Braun Felix, Folseraas Trine, Hov Johannes R, Melum Espen, Bacher Petra, Sterneck Martina, Weismüller Tobias J, Lenzen Henrike, Bokemeyer Bernd, Howie Bryan, Robins Harlan S, Röcken Christoph, Schreiber Stefan, Khanna Nina, Pröbstel Anne-Katrin, Schramm Christoph, Vogl Thomas, Karlsen Tom H, Franke Andre
Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein (UKSH), Kiel, Germany.
Adaptive Biotechnologies, Seattle, WA, USA.
Nat Med. 2025 Jun 11. doi: 10.1038/s41591-025-03692-w.
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein-Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3-22.9), suggesting a link between EBV and PSC.
原发性硬化性胆管炎（PSC）是一种特发性、进行性且无法治愈的肝脏疾病。在此，我们旨在对PSC中的适应性免疫反应进行系统分析。通过对504例PSC患者和904例健康对照的T细胞库进行分析，我们鉴定出1008种与PSC相关的克隆型。这些克隆型中的很大一部分受已知的PSC人类白细胞抗原易感等位基因限制，并且已知靶向爱泼斯坦 - 巴尔病毒（EBV）表位。我们进一步利用噬菌体免疫沉淀测序来确定120例PSC患者和202例健康对照的抗体表位库，结果显示PSC中抗EBV反应的负担高于对照。从PSC肝脏中的B细胞分离出的EBV特异性单克隆抗体证实了针对EBV的B细胞和T细胞的趋同反应。通过分析超过1.16亿人的电子健康记录，我们发现传染性单核细胞增多症与PSC之间存在关联（优势比，12；95%置信区间，6.3 - 22.9），提示EBV与PSC之间存在联系。
