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TNFRSF13B Variant-Induced TACI Dysregulation Underlies CAEBV Pathogenesis
Xinyue Deng1,2, Qiang Gao1,2, Kefeng Shen1,2
1Department of Hematology, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Journal of Clinical Immunology
|January 3, 2026
Summary
TNFRSF13B variants drive Epstein-Barr virus (EBV) reactivation by altering TACI signaling, increasing viral load and IL-10. Targeting TACI shows promise for controlling EBV infection and chronic active EBV disease (CAEBV).
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- Transmembrane activator and CAML interactor (TACI), encoded by TNFRSF13B, is crucial for immune responses.
- TNFRSF13B exon 2 variants were previously linked to chronic active Epstein-Barr virus disease (CAEBV).
Purpose of the Study:
- To elucidate the role of TNFRSF13B variants in CAEBV pathogenesis.
- To explore targeting TNFRSF13B/TACI as a therapeutic strategy against Epstein-Barr virus (EBV) infection.
Main Methods:
- CRISPR/Cas9 was used to create lymphoblastoid cell line (LCL) models with homozygous TNFRSF13B exon 2 frameshift mutations.
- Immunological assays, transcriptomic analysis, and gene silencing were performed on LCL models.
- TACI ligands, a TLR9 agonist, and BAFF trimer were used to modulate TACI signaling and EBV activity.
Main Results:
- TNFRSF13B exon 2 frameshift mutations increased TACI-short isoforms, activating NF-κB, MAPK, and Rho pathways.
- This led to EBV lytic reactivation, increased viral load, and elevated viral IL-10, explaining CAEBV susceptibility.
- BAFF trimer, an indirect TACI inhibitor, suppressed the EBV lytic program.
Conclusions:
- TNFRSF13B variants significantly impact EBV infection and host immunity, contributing to CAEBV pathogenesis.
- Altered TACI signaling due to TNFRSF13B variants promotes EBV lytic reactivation.
- Targeting TNFRSF13B/TACI presents a potential therapeutic avenue for EBV-related diseases.
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