Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency
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Le résumé fourni par la source
Abstract X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in the SH2D1A or XIAP genes, are characterized by the inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases in each, lymphomas occur at high rates with XLP-1 but not with XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis, in contrast to all other described congenital conditions that result in heightened susceptibility to EBV, remains a key open question. To gain insights, we cross-compared newly EBV infected versus immune stimulated B-cells from XLP-2 patients or upon XIAP CRISPR knockout, relative to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected primary human B-cells, though had no impact on proliferation of B-cells stimulated by CD40 ligand and interleukin-21 or upon established EBV-immortalized lymphoblastoid cell lines (LCLs). B-cells from XLP-2 patients or in which XIAP was depleted by CRISPR editing exhibited a markedly lower EBV transformation efficiency than healthy control B-cells. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, whose effects on transforming B-cell death were counteracted by XIAP. In the absence of XIAP, EBV infection triggered high rates of apoptosis, not seen with CD40L/IL-21 stimulation. Moreover, inflammatory cytokines are present at high levels in XLP-2 patient serum with fulminant EBV infection, which heightened apoptosis induction in newly EBV-infected cells. These findings highlight the crucial role of XIAP in supporting early stages of EBV-driven B-cell immortalization and provide insights into the absence of EBV+ lymphoma in XLP-2 patients. Key points XIAP loss-of-function markedly impairs EBV+ B-cells outgrowth over the first week post-infection, particularly in the presence of IFN-γ. XIAP mutation impedes EBV-driven B-cell transformation by potentiating p53-driven caspase activation and apoptosis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency
- Date Crossref
- 18/01/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Brigham and Women's Hospital Department of Medicine pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Boston Children's Hospital Department of Pediatrics Harvard Medical School pays non établi dans la noticeÉtablissement de santé
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Boston Children's Museum pays non établi dans la noticeInstitution
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Broad Institute Center for Integrated Solutions for Infectious Diseases pays non établi dans la noticeOrganisation à but non lucratif
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Harvard Program in Virology pays non établi dans la noticeInstitution
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Department of Cell Biology pays non établi dans la noticeInstitution
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Harvard Medical School pays non établi dans la noticeInstitution
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Department of Microbiology pays non établi dans la noticeInstitution
Department of Medicine — Brigham and Women's Hospital, Harvard University et Department of Pediatrics Harvard Medical School — Boston Children's Hospital, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.