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• W4380079350 abstract "Introduction: Chronic hepatitis C virus (HCV) infection leads to a complex interplay with adaptive immune cells that may result in B cell dyscrasias such as type II mixed cryoglobulinemia and lymphoma. The introduction of direct-acting antiviral (DAA) therapy has reduced the burden of severe liver damage and its clinical consequences. However, the effect of viral elimination on extrahepatic manifestations of HCV such as the accompanying B cell dyscrasia remains to be defined. Methods: We sequenced B cell repertoires in patients with chronic HCV infection and HCV patients with a sustained virological response (SVR) after DAA therapy. This data set was mined for highly neutralizing HCV antibodies and compared to a diffuse large B cell lymphoma data set. The TKO model was used to test signaling strength of selected B cell receptors (BCRs) in vitro. Single-cell RNA sequencing of chronic HCV and HCV SVR samples was performed to analyze the transcriptome of B cells with HCV-neutralizing antigen receptor. Results: The majority of HCV patients showed a B cell fingerprint with high richness and somatic hypermutation. Convergence to specific immunoglobulin genes produced complementarity-determining region 3 (CDR3) sequence networks with high connectivity. IGHV1-69 CDR1 and CDR3 mutations characterizing highly neutralizing HCV antibodies corresponded to recurrent point mutations found in the clonotypic BCRs of high-grade lymphomas. These mutations did not confer autonomous BCR signaling but lowered the threshold for activation-induced BCR signaling. In addition, B cells carrying these point mutations showed a persisting oncogenic transcriptome signature with dysregulation in signaling nodes such as CARD11, MALT1, RelB and MAPK, and NFAT pathways. Conclusions: We provide evidence that lymphoma-like cells may derive from the anti-HCV immune response. In many patients, these cells persist for years after SVR and can be interpreted as mechanistic basis for HCV-related B cell dyscrasias and increased lymphoma risk even beyond viral elimination. The research was funded by: The research was funded by Deutsche Forschungsgemeinschaft (DFG). Grant numbers: SFB841 and DFG BI 1711/4-1 to MB. Keywords: Non-Hodgkin (Pediatric, Adolescent, and Young Adult), Tumor Biology and Heterogeneity No conflicts of interests pertinent to the abstract." @default.
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• W4380079350 date "2023-06-01" @default.
• W4380079350 modified "2023-09-25" @default.
• W4380079350 title "B CELLS WITH VIRUS‐NEUTRALIZING IGHV1‐69 MUTATIONS SHOW LYMPHOMA‐LIKE TRANSCRIPTOMES IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION" @default.
• W4380079350 doi "https://doi.org/10.1002/hon.3165_670" @default.
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