Coexistent Alterations of BAFF and B Cell Biology Associated with CVID Complications

Background Common variable immunodeficiency (CVID) is a primary immunodeficiency marked by impaired antibody production and infection susceptibility, with about half developing noninfectious complications. B cell activating factor (BAFF) elevation and genetic variants in a BAFF receptor, transmembrane activator, and CAML interactor (TACI) frequently occur in CVID. While these findings associate with autoimmune and lymphoproliferative complications, pathogenic mechanisms remain incompletely defined. Objective This work explored 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 applied. Results CVID with autoimmune cytopenias and lymphoid hyperplasia had elevated plasma BAFF:TACI ratio and increased transitional and activated naïve B cells. Activated naïve B cells from CVID patients had increased mRNA of genes downstream of BAFF receptor (BAFF-R) that promote B cell survival. Also on these expanded subsets, BAFF-R surface protein decreased, consistent with negative feedback, while autoreactive B cell receptor (BCR) VH4-34 clonality increased. Conclusions Novel application of spectral flow cytometry, paired BCR sequencing RNA sequencing, 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 naïve B cells with reduced BAFF-R expression and BCR repertoire diversity. The expanded activated naïve 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.