GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333202/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333202GEOGSEfalseCoexistent alterations of BAFF and B cell phenotypes in complicated CVID courseBackground: 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.2026/05/29GSE333202GSM9758937GSM9758915GSM9758936GSM9758914GSM9758935GSM9758934GSM9758919GSM9758918GSM9758917GSM9758939GSM9758938GSM9758916GSM9758933GSM9758932GSM9758931GSM9758930GSM9758926GSM9758948GSM9758947GSM9758925GSM9758946GSM9758924GSM9758923GSM9758945GSM9758929GSM9758928GSM9758949GSM9758927GSM9758940GSM9758944GSM9758922GSM9758943GSM9758921GSM9758920GSM9758942GSM975894130173333202Homo sapiens