TNFSF13B

Detailed Information

The TNFSF13B gene, located on chromosome 13q32–q34, encodes B-cell activating factor (BAFF), also called BLyS. BAFF is synthesized as a type II transmembrane protein whose extracellular domain contains the canonical TNF homology domain; it assembles into trimers and can further organize into higher-order, virus-like 60-mer structures that markedly amplify its receptor-binding potency. The gene comprises six exons and, through alternative splicing, gives rise to at least three isoforms: a full-length membrane form (ΔBAFF), a soluble extracellular form (BAFF), and a distinctive nuclear isoform (Δ4BAFF). Unlike the extracellular isoforms, Δ4BAFF localizes to the nucleus and can act as a transcriptional regulator by forming complexes with the NF-κB p50 subunit to influence BAFF gene expression, a feature that contributes to its unique roles in autoimmunity and B-cell proliferative disorders.

BAFF exerts its effects via three receptors with overlapping and distinct roles: TACI (TNFRSF13B), BCMA (TNFRSF17), and the BAFF-specific receptor BAFFR (BR3). TACI and BCMA can also bind APRIL, whereas BAFFR is selective for BAFF. The receptors display stage-specific expression on B cells: BAFFR predominates on transitional and mature B cells, TACI is expressed on activated mature B cells and plasmablasts, and BCMA is enriched on long-lived plasma cells. This temporospatial receptor distribution is central to how BAFF orchestrates B-cell survival, differentiation, and humoral homeostasis.

Biological functions and signaling mechanisms

BAFF is a principal survival factor for B cells and a central regulator of peripheral B-cell homeostasis. During B-cell maturation in the bone marrow and upon migration to peripheral lymphoid organs, BAFFR signaling upregulates anti-apoptotic proteins such as Mcl-1 and Bcl-2, enabling transitional B cells to mature into follicular and marginal-zone compartments and sustaining the mature B-cell pool. Excess BAFF drives B-cell expansion and hypergammaglobulinemia and can precipitate autoimmunity, whereas BAFF deficiency or BAFFR defects markedly reduce mature B-cell numbers and impair humoral responses. In adaptive responses, BAFF contributes both by lowering activation thresholds—making B cells more responsive to antigen and co-stimulation—and by cooperating with T-cell help signals to promote plasmablast differentiation and class-switch recombination, processes essential for robust vaccine and infection-driven antibody production.

Figure 1. BAFF and APRIL signaling. BAFF is expressed as a membrane-bound trimer. (Vincent FB, et al., 2013)

Binding of BAFF trimers to BAFFR initiates a signaling cascade that prominently engages the noncanonical NF-κB pathway: recruitment and degradation of TRAF3 relieves inhibition of NF-κB2 p100 processing, allowing p52 generation and nuclear translocation to activate survival gene programs. Concurrent activation of PI3K–Akt–mTOR and ERK pathways supports metabolic reprogramming and proliferation. TACI signaling is more complex and context-dependent, recruiting TRAF6 to activate canonical NF-κB and JNK pathways and promoting activation-induced cytidine deaminase (AID) expression for somatic hypermutation and class-switch recombination; at the same time, TACI can transmit negative regulatory signals—via phosphatases such as SHP-1—to restrain BAFFR and TLR pathways and prevent uncontrolled B-cell activation. The nuclear Δ4BAFF isoform adds another regulatory layer by forming complexes with NF-κB p50 and binding κB sites in the BAFF promoter, establishing a positive feedback loop that can amplify BAFF production under inflammatory stimulation.

Physiological roles and pathological associations

Dysregulated BAFF expression undermines B-cell tolerance and is linked to a spectrum of autoimmune conditions. Elevated BAFF supports the survival of autoreactive B cells, facilitates ectopic germinal center formation in tissues such as salivary glands, and drives autoantibody production. These mechanisms help explain BAFF's involvement in diseases characterized by pathogenic humoral responses, where local or systemic BAFF overexpression promotes persistent autoantibody generation and tissue damage. Conversely, interventions that reduce BAFF activity can restore elements of immune balance but must be managed carefully because of infection risk when humoral immunity is overly suppressed.

In B-cell malignancies, tumor cells often exploit BAFF signaling for growth and survival: autocrine or microenvironmental BAFF supports malignant B-cell clones and can foster regulatory B-cell phenotypes that dampen antitumor immunity. In certain solid tumors, BAFF expression by stromal or tumor-associated myeloid cells influences immune cell recruitment and angiogenesis, and may correlate with adverse outcomes in specific cancer types. Conversely, under some circumstances, BAFF can contribute to the formation of tertiary lymphoid structures and local antitumor antibody responses, so its net effect is context-dependent and shaped by the cellular source and tumor milieu.

BAFF regulates B-cell responses to infection and plays a role in host defense: viruses that manipulate NF-κB signaling can induce BAFF to favor memory B-cell survival and viral persistence. Chronic infections and inflammatory states often show altered BAFF levels, which contribute both to hypergammaglobulinemia and to immune dysregulation. Genetic defects affecting BAFF signaling or its receptors can produce mucosal immunodeficiency with impaired IgA responses and predisposition to intestinal inflammation, illustrating BAFF's importance in barrier immunity and microbial homeostasis.

Translational implications and future directions

BAFF is an established therapeutic target. Agents that neutralize soluble BAFF or otherwise modulate its signaling have shown clinical benefit in autoimmune disease by reducing autoreactive B-cell pools, and approaches that target BAFF-related axes (including dual BAFF/APRIL inhibitors or BCMA-directed therapies) are integral to modern strategies against B-cell malignancies. However, therapeutic modulation demands precision: broad BAFF blockade may compromise protective humoral immunity and elevate infection risk, whereas selective modulation of receptor-specific interactions or tissue-targeted delivery could preserve host defenses while suppressing pathogenic responses.

Circulating BAFF and receptor expression profiles are useful biomarkers for disease activity and for guiding therapy adjustments; soluble receptor fragments and downstream signaling signatures likewise offer avenues for dynamic monitoring. Gene-based strategies that either correct BAFF pathway defects or transiently modulate BAFF expression show promise in preclinical models, but long-term safety—particularly the risk of inducing autoimmunity through sustained BAFF elevation—remains a central concern.

Research challenges

Key questions remain, including the physiological significance of BAFF higher-order assemblies versus trimers, the precise role and regulatory network of the nuclear Δ4BAFF isoform, and how cell-type and microenvironmental context dictate BAFF's pro- or anti-tumor activities. Single-cell and spatial transcriptomics approaches, combined with receptor-specific functional assays, will help resolve how BAFF signaling is wired across tissues and disease states. Translational progress will hinge on strategies that achieve spatial and receptor selectivity—preserving protective immunity while curbing pathogenic B-cell activation.