Coexistent alterations of BAFF and B-cell phenotypes in complicated CVID course.

Abstract

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. We sought to explore how coexistent changes in BAFF, its receptors, and B-cell subsets may shape CVID. Plasma protein measurement, spectral flow cytometry, and single-cell RNA sequencing were performed. 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. 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.