APRIL and BAFF Important Factors Regulating Immune Balance

Understanding the Components of the BAFF System Molecules

The BAFF system comprises essential molecules, including two ligands—BAFF and APRIL—and three receptors—BAFF-R, TACI, and BCMA. These molecules play significant roles in immune regulation. BAFF and APRIL are predominantly expressed by myeloid cells. BAFF initially exists in a membrane-bound form (mBAFF), but it also has a soluble counterpart (sBAFF). The soluble form is generated through the cleavage of mBAFF by furin convertase. sBAFF can exist as either a homotrimeric (3-mer) or oligomeric (60-mer) structure.

APRIL, much like BAFF, undergoes cleavage by furin convertase, either in the Golgi apparatus or at the cell membrane. Soluble APRIL forms homotrimers or forms multimers by binding to heparan sulfate proteoglycan (HSPG). Upon BAFF stimulation, membrane-bound BAFF-R (mBAFF-R) is shed by ADAM10 and ADAM17. TACI can also be found in a soluble form (sTACI) after ADAM10 and ADAM17 cleavage of its membrane-bound counterpart (mTACI). Notably, the activity of ADAM17 necessitates the stimulation of B cells by 60-mer BAFF.

In the case of mBCMA, it undergoes processing by γ-secretase. The cleaved ectodomains of all three receptors, including sBAFF-R, sTACI, and sBCMA, may act as soluble decoy receptors for both BAFF and APRIL. This intricate interplay between ligands and receptors within the BAFF system plays a pivotal role in immune regulation and its dysregulation can contribute to various immune-related disorders.

Introduction to APRIL

APRIL is a proliferation-inducing ligand, a pivotal member of the TNF receptor family and holds a crucial spot as a ligand of BCMA. Despite sharing 30% sequence homology with BAFF, another BCMA ligand, APRIL exhibits a higher affinity for BCMA. This affinity translates into its distinctive ability to interact effectively with BCMA, setting it apart.

In healthy human tissues, APRIL maintains relatively modest expression levels, being notably present in monocyte macrophages[2], activated T lymphocytes, dendritic cells, pancreas, spleen, and other cell types. However, its expression skyrockets in tumor tissues, signifying its potential significance in pathological contexts. Notably, APRIL exists in two biologically active forms: a soluble form with a relative molecular mass of 17k and a membrane-bound form with a relative molecular mass of 30k.

Osteoclasts (OC) are the primary culprits behind APRIL secretion, and its impact is remarkable. APRIL directly facilitates the survival of malignant plasma cells through its interactions with proteoglycans[3]. In concert with BCMA, APRIL escalates the survival capabilities of bone marrow blood cells and plasmablasts. This interaction even influences the expression of immune checkpoints, contributing to the creation of an immunosuppressive bone marrow microenvironment[4]. Such an environment may have profound implications for disease progression.

Furthermore, the binding of APRIL to BCMA triggers canonical and non-canonical NF-κB pathways, amplifying angiogenesis, metastatic migration, as well as the growth and proliferation of tumor cells. This intricate interplay between APRIL and BCMA highlights its multi-faceted role in promoting tumor progression and shaping the tumor microenvironment. Understanding these mechanisms is imperative for the development of targeted therapies against diseases where the APRIL-BCMA axis is implicated.

Introduction to BAFF

BAFF, also known as BLys, stands as a key member of the TNF family, composed of 285 amino acids, and classified as a type II transmembrane protein. With its presence spanning two forms—membrane-bound and soluble—BAFF finds primary expression on the surfaces of innate immune cells, including monocytes, macrophages, and dendritic cells. Notably, cytokines such as IFN-γ, IL-10, and G-CSF are known to elevate the expression of BAFF, underscoring its dynamic regulatory nature.

While binding BCMA with a relatively modest affinity, BAFF's influence extends beyond this interaction. It also forms connections with members of the broader TNF receptor family, such as BAFF-R (B-cell activating factor receptor) and TACI (Transmembrane activator and calcium-modulator and cytophilin ligand interactor). This intricate interplay with these receptors orchestrates a sophisticated dance that affects the survival of B cells and plasma cells[5].

Within the landscape of multiple myeloma, BAFF's production is orchestrated through autocrine and paracrine pathways, with the latter emerging as the dominant source. Upon binding with BCMA, TACI, or BAFF-R, BAFF sets in motion a cascade of signaling pathways, including the classic and non-canonical NF-κB pathways and the JNK signaling pathway. This activation induces the upregulation of anti-apoptotic proteins, while concurrently suppressing pro-apoptotic counterparts[6]. This finely tuned interplay fosters the survival and proliferation of multiple myeloma cells.

Clinical observations highlight the significance of BAFF levels. In multiple myeloma patients, circulating serum BAFF levels are markedly elevated—3- to 5-fold higher than those in healthy subjects. Notably, serum BAFF levels correlate positively with proliferation markers within myeloma cells, encompassing IL-6, IL-10, lactate dehydrogenase, C-reactive protein, and β2-microglobulin.

Interestingly, an overexpression of BAFF has been linked to the induction of multiple myeloma, while its deficiency can lead to compromised immune function and immunodeficiency diseases. These multifaceted interactions underscore the pivotal role of BAFF in immune homeostasis and its implications in various diseases[7].

The Role of APRIL and BAFF in Multiple Myeloma

Multiple myeloma (Multiple Myeloma, MM) is a malignant bone marrow plasma cell disease that mainly affects the immune system and bones. The tumor begins in the bone marrow with plasma cells, a special type of white blood cell that multiply abnormally and accumulate in the bone marrow, interfering with the production of normal blood-forming cells.

Clinical symptoms of multiple myeloma include bone pain, anemia, easy fractures, and fatigue. Due to the buildup of tumor cells, bones may be destroyed, resulting in bone pain and susceptibility to fractures. In addition, tumor cells can also interfere with the function of the immune system, increasing the risk of infection.

In multiple myeloma, APRIL and BAFF play the following key roles:

1. Promote cell survival and proliferation:

APRIL and BAFF can combine with their receptors (such as BCMA, TACI, BAFF-R) to activate downstream signaling pathways, thereby promoting the survival and proliferation of multiple myeloma cells.

This signaling may inhibit apoptosis, making tumor cells more able to survive in the bone marrow environment.

1. Modulation of immune response and escape:

The abnormal expression of APRIL and BAFF may affect the function of immune cells, such as inhibiting the production and function of normal B cells, thereby interfering with the immune response.

At the same time, they may help multiple myeloma cells escape the immune system's surveillance, leading to tumor development.

1. Interact with the bone marrow microenvironment:

APRIL and BAFF interact with cells in the bone marrow microenvironment, such as bone marrow stromal cells and other immune cells.

This interaction may play an important role in the survival and expansion of multiple myeloma cells in the bone marrow, as well as adverse changes in the bone marrow environment.

In summary, APRIL and BAFF regulate the survival, proliferation, differentiation and immune response of B cells by interacting with their receptors in multiple myeloma. Their abnormal expression may be related to the development, severity and prognosis of multiple myeloma. Therefore, studying how to interfere with the action of APRIL and BAFF, and their interactions with tumor cells, immune cells, and the bone marrow microenvironment may help to develop new therapeutic strategies to improve the prognosis and survival of multiple myeloma patients.

APRIL and BAFF Participate in the Signaling Pathway of BCMA

BCMA (B cell maturation antigen) engages with two activating ligands: a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF). These ligands are primarily secreted by bone marrow stromal cells, osteoclasts, and macrophages in a paracrine manner within the bone marrow environment [9-10]. APRIL exhibits a higher binding affinity to BCMA than BAFF and also binds to TACI, while BAFF has a greater selectivity for BAFF-R [11]. APRIL is particularly pertinent to plasma cells (PCs) and is linked to downstream pathophysiological activities. Notably, xenografted MM cell lines showed significantly reduced growth in APRIL−/− mice, suggesting its role in MM progression [12]. In MM patients, elevated serum levels of APRIL and BAFF, up to 5-fold that of healthy controls, are detected, with higher concentrations correlating to advanced MM stages [12]. Augmented MM-induced osteoclast-produced APRIL fosters an immunosuppressive bone marrow microenvironment, indicating that incorporating APRIL-blocking monoclonal antibodies (mAbs) into BCMA-directed immunotherapies might enhance antibody-dependent cell-mediated cytotoxicity (ADCC) against MM cells.

Following ligand binding, BCMA triggers multiple growth and survival signaling cascades within MM cells, predominantly the nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) pathway. This includes rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) and phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt) pathways. These pathways drive proliferation by influencing cell cycle checkpoints, enhance survival through upregulating anti-apoptotic proteins (e.g., Mcl-1, BCL-2, BCL-XL), and induce the production of molecules vital for cell adhesion (e.g., ICAM-I), angiogenesis (e.g., VEGF, IL-8), and immune suppression (e.g., IL-10, PD-L1, TGF-β) [13]. Intriguingly, BCMA overexpression can activate NF-κB and MAPK pathways even without APRIL or BAFF stimulation [14]. Further interplays between APRIL/BCMA signaling and other pathways are evident. For instance, APRIL interacts with CD138/syndecan-1 and heparan sulfate proteoglycans (HSPG) to support MM cell proliferation and survival [15]. Concurrent FGF-R3 and JAK2 blockade leads to BCMA downregulation [16]. Additionally, in vitro studies highlight BCMA's association with interferon regulatory factor-4 (IRF-4), a pivotal transcription factor in MM cell survival [17]. These insights emphasize BCMA's intricate role in MM oncogenesis.

APRIL and BAFF Protein

Recombinant Human APRIL Protein

Click here for more APRIL

Synonym: Tumor necrosis factor ligand superfamily member 13; A proliferation-inducing ligand; APRIL; TNF- and APOL-related leukocyte expressed ligand 2; TALL-2; TNF-related death ligand 1; TRDL-1; CD256; TNFSF13

Recombinant Human BAFF Protein

Click here for more BAFF

Synonym:BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNFSF20, TNFSF13B, B-cell Activating Factor.

References:

 

[1] Sakai J, Akkoyunlu M. The Role of BAFF System Molecules in Host Response to Pathogens. Clin Microbiol Rev. 2017 Oct;30(4):991-1014. doi: 10.1128/CMR.00046-17. PMID: 28855265; PMCID: PMC5608883.
[2] Lee H C, Raje N S, Landgren O, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma[J]. Leukemia, 2020: 1-4.
[3] Gavriatopoulou M, Ntanasis-Stathopoulos I, Dimopoulos M A, et al. Anti-BCMA antibodies in the future management of multiple myeloma[J]. Expert review of anticancer therapy, 2019, 19(4): 319-326.
[4] Shah N, Chari A, Scott E, et al. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches[J]. Leukemia, 2020: 1-21.
[5] Mackay F, Browning J L. BAFF: a fundamental survival factor for B cells[J]. Nature Reviews Immunology, 2002, 2(7): 465-475.
[6] Tai Y T, Anderson K C. B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma[J]. Expert opinion on biological therapy, 2019, 19(11): 1143-1156.
[7] Cho S F, Anderson K C, Tai Y T. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy[J]. Frontiers in immunology, 2018, 9: 1821.
[8] Hengeveld, P., Kersten, M. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?. Blood Cancer Journal 5, e282 (2015).
[9] Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127(25):3225-3236. doi:10.1182/blood-2016-01-691162
[10] Tai YT, Li XF, Breitkreutz I, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2006;66(13):6675-6682. doi:10.1158/0008-5472.CAN-06-0190
[11] Day ES, Cachero TG, Qian F, et al. Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry. 2005;44(6):1919-1931. doi:10.1021/bi048227k
[12] Pan J, Sun Y, Zhang N, et al. Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance. Oncol Lett. 2017;14(3):2657-2662. doi:10.3892/ol.2017.6528
[13] Tai YT, Anderson KC. B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma. Expert Opin Biol Ther. 2019;19(11):1143-1156. doi:10.1080/14712598.2019.1641196
[14] Hatzoglou A, Roussel J, Bourgeade MF, et al. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol. 2000;165(3):1322-1330. doi:10.4049/jimmunol.165.3.1322
[15] Hendriks J, Planelles L, de Jong-Odding J, et al. Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death Differ. 2005;12(6):637-648. doi:10.1038/sj.cdd.4401647
[16] Cassinelli G, Ronchetti D, Laccabue D, et al. Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting. Biochem Pharmacol. 2009;78(9):1139-1147. doi:10.1016/j.bcp.2009.06.023
[17] Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454(7201):226-231. doi:10.1038/nature07064
[18] Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13(1):125. Published 2020 Sep 17. doi:10.1186/s13045-020-00962-7