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

ABSTRACT 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.