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Coexistent alterations of BAFF and B-cell phenotypes in complicated CVID course
Erik M Matson1, Matthew S Ware1, Feng Feng2
1Pulmonary Center, Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass.
Insights
Common variable immunodeficiency (CVID) involves immune system dysregulation. Elevated BAFF and altered B cell subsets contribute to autoimmune and lymphoproliferative complications in CVID patients.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired antibody production and susceptibility to infections.
- Approximately 50% of CVID patients develop non-infectious complications, including autoimmune disorders and lymphoproliferative conditions.
- Elevated B-cell activating factor (BAFF) levels and genetic variations in its receptor, TACI, are frequently observed in CVID, but their precise role in pathogenesis remains unclear.
Purpose of the Study:
- To investigate the interplay between BAFF, its receptors, and B cell subsets in the context of CVID.
- To elucidate the molecular mechanisms underlying autoimmune and lymphoproliferative complications in CVID.
Main Methods:
- Plasma protein analysis using ELISAs.
- High-dimensional spectral flow cytometry for detailed B cell subset characterization.
- Single-cell RNA sequencing (scRNA-seq) coupled with B cell receptor (BCR) repertoire analysis.
Main Results:
- CVID patients with autoimmune cytopenias and lymphoid hyperplasia exhibited elevated plasma BAFF and BAFF:TACI ratios.
- Expanded populations of transitional and activated naive B cells were observed in CVID patients.
- Activated naive B cells showed increased expression of BAFF-R-driven survival genes, decreased BAFF-R surface expression, and increased autoreactive BCR clonality (VH4-34).
Conclusions:
- CVID with autoimmune and lymphoproliferative features is associated with dysregulation of BAFF signaling and B cell subsets.
- The findings highlight a complex interplay involving increased BAFF, altered B cell populations with impaired BAFF-R feedback, and expanded autoreactive B cells.
- Further research into the convergence of BAFF, its receptors, and B cell subset abnormalities is warranted for understanding CVID pathogenesis.
Background:
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.
Objective:
We sought to explore 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 performed.
Results:
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.
Conclusions:
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.
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