TNFSF13

Detailed Information

The TNFSF13 gene encodes a member of the tumor necrosis factor (TNF) ligand superfamily widely known as APRIL (A Proliferation-Inducing Ligand), designated CD256 in differentiation nomenclature. Located on human chromosome 17p13.1, TNFSF13 is unique in that it can undergo read-through transcription with the adjacent TNFSF12 gene, generating a TNFSF12-TNFSF13 fusion transcript, adding complexity to its regulation. APRIL is initially synthesized as a transmembrane protein and subsequently cleaved by furin proteases to produce a soluble, active cytokine. Structurally, APRIL contains a typical TNF homology domain and forms homotrimers, a configuration essential for receptor interaction.

APRIL's biological activity is primarily mediated through two specific receptors: B cell maturation antigen (BCMA/TNFRSF17) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI/TNFRSF13B). Both receptors are mainly expressed on B cells, though at different stages: BCMA is highly expressed in plasma cells, while TACI is present in memory B cells and plasma cell precursors. APRIL binds BCMA with higher affinity than TACI and can form heterotrimers that simultaneously engage both receptors. Additionally, APRIL interacts with heparan sulfate proteoglycans (HSPGs), promoting its accumulation on the cell surface and potentially enhancing receptor-mediated signaling.

Biological Functions and Immune Regulation

APRIL plays a central role in humoral immunity, acting as a key regulator of B cell survival, proliferation, and differentiation. In germinal center responses, APRIL produced by macrophages and dendritic cells binds TACI and BCMA on B cells, promoting differentiation into long-lived plasma cells that migrate to the bone marrow to sustain continuous antibody production. Knockout studies indicate that while APRIL-deficient mice can initiate immune responses, plasma cell survival is reduced, leading to rapid declines in antibody levels. In T cell-independent responses, especially against polysaccharide antigens, APRIL directly activates B cells, supporting defense against encapsulated bacteria independently of T cell help.

Figure 1. Effects of BAFF and APRIL on immune homeostasis. (Ullah MA, et al., 2023)

Beyond promoting B cell responses, APRIL contributes to immune tolerance. In the intestinal mucosa, APRIL is expressed by epithelial and stromal cells and induces IgA class switching, facilitating secretory IgA production to maintain mucosal barrier integrity. Microbiota can stimulate APRIL expression, while APRIL deficiency leads to reduced IgA levels and microbial dysbiosis. APRIL also modulates regulatory B cell (Breg) functions, which secrete inhibitory cytokines such as IL-10 to maintain immune tolerance; dysregulation of these pathways is associated with autoimmune disease.

APRIL exhibits functions beyond immunity. In the nervous system, it is expressed by neurons and glial cells and may influence neurodevelopment and tissue repair. During liver regeneration, APRIL expression increases and promotes hepatocyte proliferation. In the tumor microenvironment, APRIL affects tumor cell growth, angiogenesis, and matrix remodeling, highlighting its multifunctional role in tissue repair and tumorigenesis.

Pathological Mechanisms and Disease Associations

Disruption of APRIL signaling is implicated in several immune disorders. In common variable immunodeficiency (CVID), mutations in TACI impair APRIL-mediated signaling, resulting in blocked B cell differentiation, reduced antibody production, and recurrent infections. Conversely, autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show elevated serum APRIL levels, correlating with disease activity and autoantibody titers. TNFSF13 polymorphisms are associated with SLE susceptibility, emphasizing the delicate balance APRIL maintains in immune homeostasis.

APRIL exhibits dual roles in cancer. As a B cell growth factor, it is overexpressed in B cell malignancies such as multiple myeloma, Hodgkin lymphoma, and chronic lymphocytic leukemia. In multiple myeloma, tumor cells express both APRIL and BCMA and secrete APRIL to establish autocrine loops that enhance proliferation and drug resistance. In solid tumors, high TNFSF13 expression, as observed in breast cancer, correlates with tumor differentiation, lymph node metastasis, and poor prognosis. Mechanistically, APRIL promotes tumor cell survival through PI3K/Akt and NF-κB signaling and enhances invasive capacity by upregulating matrix metalloproteinases.

APRIL is implicated in neurodegenerative diseases, with elevated cerebrospinal fluid levels observed in Alzheimer's disease correlating with neuroinflammation markers. In chronic kidney disease, increased serum APRIL levels associate with declining renal function, reflecting persistent immune activation. Certain infectious diseases, such as HIV infection, show altered APRIL expression, contributing to B cell dysfunction and impaired immune reconstitution.

Clinical Translation and Therapeutic Potential

APRIL signaling has become a therapeutic target in multiple diseases. In multiple myeloma, BCMA-targeted chimeric antigen receptor T cell (CAR-T) therapies and antibody-drug conjugates (ADC) have advanced, including belantamab mafodotin, approved for relapsed or refractory cases. Monoclonal antibodies targeting APRIL itself, such as BION-1301, have completed early clinical trials, showing reductions in free APRIL levels and suppression of myeloma cell growth. In autoimmune diseases, agents like atacicept (TACI-Fc fusion protein) block both APRIL and BAFF, reducing autoantibodies and proteinuria in SLE and IgA nephropathy studies.

Serum APRIL levels serve as biomarkers for disease activity in autoimmune disorders and B cell malignancies. High TNFSF13 expression in breast cancer correlates with shorter survival, suggesting its potential utility in prognosis and treatment guidance. Soluble BCMA (sBCMA) serves as an alternative biomarker of APRIL pathway activation, demonstrating high sensitivity and specificity for monitoring therapeutic response in multiple myeloma.

Recombinant APRIL protein is being explored as a vaccine adjuvant due to its ability to enhance B cell and plasma cell responses. Animal studies show that APRIL can boost immunogenicity to protein and polysaccharide antigens and promote durable humoral immunity. In aged models, APRIL adjuvants partially restore age-related declines in antibody responses, indicating potential for elderly vaccine development, though autoimmune risks require careful assessment.

In summary, TNFSF13/APRIL is a central regulator of B cell biology, playing multifaceted roles in humoral immunity, autoimmunity, and tumor progression. Understanding its signaling pathways provides novel therapeutic opportunities, from targeted drugs to prognostic biomarkers, and may guide precision interventions to improve patient outcomes across diverse diseases.