Rare But Specific B-Cell Receptor Reactivity Against Coxsackievirus A24 in Primary Central Nervous System Lymphomas.

Introduction: Primary central nervous system lymphoma (PCNSL) remains a distinct and aggressive malignancy whose underlying antigenic triggers are largely unknown. While autoantigens such as neurabin-I and SAMD14 have been implicated, the potential role of infectious agents in driving clonal B-cell receptor selection within the central nervous system remains less understood. Methods: A viral proteome microarray screening approach encompassing 158 viral entities was utilized to test tumor-derived recombinant B-cell receptors from PCNSL. Furthermore, we analyzed a validation cohort comprising 22 PCNSL patients and tested expanded control sera from 188 healthy individuals. Functional assays were performed to confirm B-cell receptor activation and downstream signaling upon cognate antigen engagement. Results: Screening identified a distinct B-cell receptor reactivity directed against Coxsackievirus A24 in a PCNSL case, which was completely absent across non-PCNSL lymphomas. Validation testing in an independent cohort confirmed rare reactivity (1/22, 4.55%). Control serum analysis revealed weak reactivity in 1 out of 188 healthy individuals (0.53%). Functional assays demonstrated that the Coxsackievirus A24-derived antigen is capable of triggering antigen-specific receptor signaling. Conclusion: We report the first evidence linking PCNSL B-cell receptor reactivity to a viral antigen, identifying Coxsackievirus A24 as a rare ligand. While functional assays confirm the capacity for receptor activation, the findings must be interpreted cautiously as hypothesis-generating. Further investigation in larger independent cohorts is required to determine whether viral antigens play any meaningful pathogenic role in this malignancy. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.