Academic Journal
Coexistent alterations of BAFF and B-cell phenotypes in complicated CVID course.
| Τίτλος: | Coexistent alterations of BAFF and B-cell phenotypes in complicated CVID course. |
|---|---|
| Συγγραφείς: | Matson EM; Pulmonary Center, Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Ware MS; Pulmonary Center, Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Feng F; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Yu L; Department of Computational Biomedicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Beane JE; Department of Computational Biomedicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Belkina AC; Pulmonary Center, Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass; Flow Cytometry Core Facility, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass., Maglione PJ; Pulmonary Center, Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass. Electronic address: pmaglion@bu.edu. |
| Πηγή: | The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2026 Sep; Vol. 158 (3), pp. 908-921.e6. Date of Electronic Publication: 2026 May 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Mosby Country of Publication: United States NLM ID: 1275002 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-6825 (Electronic) Linking ISSN: 00916749 NLM ISO Abbreviation: J Allergy Clin Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: St Louis, Mosby. |
| Ιατρικοί όροι (MeSH): | B-Cell Activating Factor*/immunology , B-Cell Activating Factor*/blood , B-Cell Activating Factor*/genetics , Common Variable Immunodeficiency*/immunology , Common Variable Immunodeficiency*/genetics , B-Lymphocytes*/immunology , B-Lymphocyte Subsets*/immunology, B-Cell Activation Factor Receptor/genetics ; B-Cell Activation Factor Receptor/immunology ; Transmembrane Activator and CAML Interactor Protein/genetics ; Transmembrane Activator and CAML Interactor Protein/immunology ; Transmembrane Activator and CAML Interactor Protein/blood ; Humans ; Female ; Phenotype ; Male ; Adult ; Lymphocyte Activation ; Cytopenia |
| Περίληψη: | Background: Common variable immunodeficiency (CVID) is a primary immunodeficiency marked by impaired antibody production and infection susceptibility, with about half the patients developing noninfectious complications. B-cell activating factor (BAFF) elevation and genetic variants in a BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), frequently occur in CVID. Although these findings associate with autoimmune and lymphoproliferative complications, pathogenic mechanisms remain incompletely defined. Objective: We sought to explore how coexistent changes in BAFF, its receptors, and B-cell subsets may shape CVID. Methods: Plasma protein measurement, spectral flow cytometry, and single-cell RNA sequencing were performed. Results: CVID with autoimmune cytopenia and lymphoid hyperplasia had elevated plasma BAFF:TACI ratio and increased transitional and activated naive B cells. Activated naive B cells from patients with CVID had increased mRNA of genes downstream of BAFF-R that promote B-cell survival. Also, on these expanded subsets, BAFF-R surface protein decreased, consistent with negative feedback, whereas autoreactive B-cell receptor (BCR) VH4-34 clonality increased. Conclusions: Spectral flow cytometry, paired BCR-sequencing RNA-seq, and measurement of BAFF and related proteins in plasma found CVID with autoimmune and lymphoproliferative complications to be marked by coexistent BAFF and B-cell subset dysregulation. This included increased plasma BAFF, BAFF:TACI ratio, and transitional and activated naive B cells with reduced BAFF-R expression and BCR repertoire diversity. The expanded activated naive B-cell subset in CVID had increased expression of BAFF-R-driven genes that subvert B-cell tolerance as well as increased autoreactive VH4-34 clonality. Convergence of BAFF, its receptors, and B-cell subset dysregulation should be further explored in CVID. (Copyright © 2026 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Disclosure statement This study was supported by the National Institutes of Health (grant nos. K23 AI137187 and R01 MD017816 to P.J.M. and grant no. T32 AI007309 to E.M.M.) and by a faculty development award from the American Academy of Allergy, Asthma & Immunology. Disclosure of potential conflict of interest: P. J. Maglione has served as a consultant for ADMA Biologics, Novartis, Pharming, and Sanofi; and has received investigator-initiated research grants from Pharming and Takeda. The rest of the authors declare that they have no relevant conflicts of interest. |
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| Grant Information: | K23 AI137183 United States AI NIAID NIH HHS; R01 MD017816 United States MD NIMHD NIH HHS; T32 AI007309 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: B-cell dysregulation; BAFF; Common variable immunodeficiency (CVID); TACI; activated naive B cells; apoptosis; autoimmunity; cell survival; single-cell RNA sequencing; transitional B cells |
| Substance Nomenclature: | 0 (B-Cell Activating Factor) 0 (B-Cell Activation Factor Receptor) 0 (TNFSF13B protein, human) 0 (Transmembrane Activator and CAML Interactor Protein) 0 (TNFRSF13B protein, human) 0 (TNFRSF13C protein, human) |
| Entry Date(s): | Date Created: 20260531 Date Completed: 20260904 Latest Revision: 20260922 |
| Update Code: | 20260922 |
| PubMed Central ID: | PMC13367221 |
| DOI: | 10.1016/j.jaci.2026.04.029 |
| PMID: | 42219089 |
| Βάση Δεδομένων: | MEDLINE |
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