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

Background: Common variable immunodeficiency (CVID) is a primary immunodeficiency marked by impaired antibody production and infection susceptibility, with about half developing non-infectious complications. 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 was 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-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 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.