Molecular and immunological mechanisms of B cell activating factor-driven B cell dysregulation in CVID
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Abstract
Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency, characterized by impaired antibody production, recurrent infections, and non-infectious complications such as autoimmune cytopenia (AIC) and interstitial lung disease (ILD). Among these, ILD is a significant cause of morbidity and mortality, yet its precise pathophysiology remains poorly understood. ILD in CVID is associated with profound pulmonary infiltration of T and B cells, granulomatous inflammation, and dysregulated B cell activation, suggesting that intrinsic immune abnormalities contribute to its development. B cell depletion therapy ameliorates disease in a subset of CVID ILD, yet variability in treatment response highlights gaps in understanding the mechanisms underlying ILD progression and recurrence. Identifying biomarkers and molecular pathways that distinguish CVID ILD subtypes and predict treatment response remains an unmet clinical need.One key contributor to B cell dysregulation in CVID is B cell activating factor (BAFF), a cytokine that promotes B cell activation and survival through its three receptors: BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA). Genetic variants in TNFRSF13B, the gene encoding TACI, are frequently found in CVID patients with autoimmune and lymphoproliferative complications, yet how these variants modulate BAFF signaling remains incompletely understood. Notably, CVID patients with ILD and AIC exhibit elevated plasma BAFF levels and an increased BAFF:TACI ratio, suggesting that excessive BAFF stimulation may contribute to immune dysregulation. Given the role of BAFF in promoting B cell survival, persistent BAFF elevation may sustain autoreactive B cells and drive disease progression.
To investigate the molecular mechanisms underlying BAFF signaling, we employed cell-line expression systems of recombinant BAFF receptors and CVID-associated TNFRSF13B variants in a controlled setting. We developed luciferase-based NF-kB reporter assays to assess BAFF-R and TACI signaling in response to recombinant BAFF, soluble TACI, and plasma from CVID subjects with high BAFF:TACI ratios. These biochemical studies provide insights into receptor-ligand interactions, BAFF-mediated signaling cascades, and the regulatory function of soluble TACI. By elucidating how TNFRSF13B variants influence BAFF neutralization and signaling, this study enhances understanding of BAFF’s role in CVID pathogenesis and its potential as a therapeutic target.
To translate these molecular insights into clinically relevant immune alterations, we performed plasma protein profiling, spectral flow cytometry, and single-cell RNA sequencing in a clinically defined CVID cohort. Our findings reveal an expansion of transitional and activated naïve B cells in CVID subjects with autoimmune and lymphoproliferative complications. These cells exhibit reduced BAFF-R expression and upregulation of genes associated with B cell activation and survival, including anti-apoptotic Bcl-2 family members. Single-cell transcriptomic analysis further identifies enrichment of autoreactivity-associated VH4-34+ B cells, a subset known to escape immune tolerance and contribute to autoimmunity. These findings suggest that BAFF-driven B cell dysregulation underlies autoimmune and lymphoproliferative complications in CVID.
Collectively, our findings provide evidence of heightened BAFF signaling, elevated BAFF to TACI ratio, and altered transcriptional profiles of transitional and activated naïve B cells in CVID patients with more complicated disease course. These results underscore the complex interplay between BAFF dysregulation and B cell abnormalities in CVID, warranting further exploration into its broader implications for disease progression and management. Future studies integrating longitudinal patient data with mechanistic insights from functional biochemical and transcriptomic analyses will be essential to refine therapeutic strategies and improve patient outcomes.
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2025