The Journal of allergy and clinical immunology · 2026
Coexistent alterations of BAFF and B-cell phenotypes in complicated CVID course.
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Matson Erik M, Ware Matthew S, Feng Feng, Yu Lingge, Beane Jennifer E, Belkina Anna C, Maglione Paul J
Аннотация
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.
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.