B cell-activating factor (BAFF) and its structural homologue A proliferation-inducing ligand (APRIL) are type II transmembrane proteins belonging to the tumour necrosis factor (TNF) cytokine superfamily (25, 26). Although they share the same structure, their functions are quite different. BAFF can be synthesized as a membrane-bound form (mBAFF) and converted into a secreted form (sBAFF), which is the main form in circulation (27, 28). BAFF is mainly expressed by immune cells, such as monocytes, macrophages, dendritic cells, and neutrophils (29, 30). Moreover, BAFF can be produced by non-immune cells, including adipocytes, keratinocytes, and intestinal epithelial cells (31, 32). BAFF expression is upregulated by interleukin (IL)-10, interferons (IFNs), toll-like receptor (TLR) agonists, granulocyte colony-stimulating factor (G-CSF), and by the activation of interferon regulatory factors (IRFs), such as IRF1 and IRF2. Conversely, IRF4 and IRF8 negatively regulate BAFF expression (33, 34). APRIL can also be synthesized by various types of immune cells in both membrane-bound and secreted form. Similarly, APRIL expression is regulated by IL-10, IFNs, G-CSF, TLR, and IRFs (9, 35–37).

BAFF receptor (BAFFR), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) are type III membrane proteins with distinct but complementary effects (38, 39). These three receptors, like their ligands, can be converted from the membrane-bound form into the secreted form (40–42). BCMA and TACI share two common ligands, BAFF and APRIL, whereas BAFFR has only one ligand, BAFF (43, 44). Moreover, BCMA shows a lower affinity for BAFF compared with that for APRIL, whereas TACI has an equal affinity for both ligands (45). In contrast to the widespread expression of ligands, the expression of these three receptors is restricted to specific immune cells. Although B cells can express all three receptors, their expression varies during B cell maturation stage (37, 46, 47). In contrast to B cells, human T cells only express BAFFR, whereas mouse T cells express BAFFR and TACI (47–49).

B cell-activating factor (BAFF) system molecules modulate a variety of biological processes, including cell survival, differentiation, and other effector functions, as demonstrated in some autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), and systemic sclerosis (SSc) (50–52). BAFF receptor (BAFFR) interaction with BAFF activates both the classical and alternative transcription factor nuclear factor-kappa B (NF-κB) pathways, whereas B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) linked to BAFF only activates the classical NF-κB pathway (29, 53). Furthermore, BAFF activates the phosphoinositide-3-kinase (PI3K) dependent signalling cascade to support cell survival (54) ( Figure 1 ). However, most immunobiological findings related to molecules of the BAFF system have been obtained using transgenic mouse models.

Systemic lupus erythematosus (SLE) is an idiopathic, complex autoimmune disease that involves a wide array of organs and predominantly affects females (105). Approximately 70% of the patients experience some degree of skin involvement (106). Elevated BAFF levels have been detected in the skin, serum, urine, and kidneys of patients with SLE, with correlations to disease pathology and autoantibody titres in both human and murine models (12, 107–110). However, the correlation between circulating BAFF levels and anti-double-stranded DNA (anti-dsDNA) titers remains controversial. This contradiction may be attributed to the different detection methods (111, 112). BAFF Tg mice with BAFF overexpression exhibit SLE-like manifestations, such as hypergammaglobulinemia, increased serum immune complexes, levels of rheumatoid factor (RF) and anti-dsDNA, as well as renal Ig deposits (69). Moreover, BAFF overexpression has been observed in other spontaneous SLE-prone mice (39). Consistently, BAFF blockade attenuates symptoms and disease activity in SLE mice, thereby improving survival (113, 114). Excess BAFF may participate in the development of SLE through supporting autoreactive B cells survival (115). Lupus nephritis (LN) is a severe complication of SLE, characterized by kidney inflammation due to autoimmune-mediated damage, primarily affecting the glomeruli. Glomerular APRIL and BAFF levels are significantly elevated in patients with LN (95). Furthermore, BAFF levels in the kidneys of LN mice are correlated with disease activity and the histopathological activity index (116). BAFF promotes LN by inducing a tertiary lymphoid structure in the kidney and modulating the position of glomerular T cells (117). In addition to LN, cutaneous symptoms are also observed in many patients with SLE. The levels of BAFF and its three receptors—BAFFR, BCMA, and TACI—are increased in patients with cutaneous lupus erythematosus (CLE). In these patients, BAFF is mainly expressed in keratinocytes, whereas the three receptors are mainly expressed in the lymphoid cells. Moreover, BAFF expression is significantly upregulated after stimulation with immunostimulatory DNA motifs in cultured keratinocytes (13, 94, 118).

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by impaired function of exocrine glands and extra glandular manifestations (119). Notably, patients with SS exhibit elevated serum and SG levels of BAFF. In addition, increased BAFF levels are strongly correlated with anti-SSA IgG/IgM and RF levels (18, 98, 120). As mentioned in Section 3.1, BAFF Tg mice overexpressing BAFF exhibit SLE-like manifestations. However, as they age, these mice acquire features of SS, such as glandular inflammation and structural destruction (18). Early BAFFR blockade alleviates SS-like syndromes in mice (121). Moreover, salivary epithelial cells in patients can secrete different forms of BAFF to participate in the pathogenesis of SS, and BAFF can also promote epithelial cell survival through autocrine signalling (122). Additionally, studies in patients with SS and mouse models have shown that BAFF is involved in the formation of germinal centre-like structures, which are important in SS pathogenesis (123–126).

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by progressive fibrosis and vasculopathy of the internal organs and skin (127). The serum levels of APRIL and BAFF are increased in patients with SSc and positively correlated with skin and pulmonary fibrosis, respectively (16, 17). Furthermore, adding anti-IgM and BAFF to a co-culture of dermal fibroblasts and peripheral B cells isolated from patients with SSc showed that BAFF enhanced the collagen-inducing effect of B cells in dermal fibroblasts (128). Tight skin (TSK/+) mice, which are genetic a murine model of SSc, develop cutaneous fibrosis and autoimmunity. Intriguingly, circulating BAFF levels and skin fibrotic cytokines are elevated in the TSK/+ mouse model. Moreover, BAFF antagonists enhance the expression of anti-fibrotic cytokines, therefore inhibiting autoantibody production, skin fibrosis, and fibrotic cytokine expression in TSK/+ mice (129). Notably, neutralisation of BAFF or deletion of the BAFF gene led to diminished fibrosis in a bleomycin-induced model of pulmonary fibrosis (130). Furthermore, a small pilot study using BLM to suppress BAFF showed an improvement in skin hardening in patients with SSc (51). The results of these studies show that the pathogenesis of SSc is complicated and involves various environmental and genetic factors, warranting further investigation in future studies.

Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by tense skin bullae and less oral involvement. These manifestations may be due to the presence of complement component C3 and IgG autoantibodies, which target the dermo–epidermal basement membrane, resulting in dermal separation (131). One study revealed increased levels of circulating BAFF in patients with BP (15). Furthermore, flow cytometric analysis confirmed elevated BAFF expression in memory and naïve B cells in patients with BP (132). Conversely, another study found that the levels of circulating BAFF molecules in healthy controls were comparable with those in patients with BP (133). This discrepancy is likely attributable to differences in disease duration. Serum APRIL levels are also increased in patients with BP (11). RTX is a third-line treatment for BP and has clinical benefits for severe BP. One study found that serum BAFF level increased after RTX treatment in patients with BP. Additionally, serum BAFF levels increased before the peripheral B cell number returned to normal, implying a relapse (134). Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used for the treatment of type 2 diabetes, increase the risk of BP (DPP4is-associated BP). BAFF expression is higher in regular BP skin (not associated with DPP4is) compared to that in DPP4i-associated BP skin (135). However, few studies have explored the role of BAFF in BP pathogenesis, with studies largely restricted to phenomenological observations. Thus, further investigation is required to determine whether and how BAFF is involved in BP pathogenesis.

Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized by erosions and flaccid blisters of the skin and the mucous membranes owing to the intra-epidermal separation of keratinocytes (136). While some studies report elevated serum APRIL levels in patients with PV, others show no significant differences, casting doubt on its role (11, 14). A similar inconsistency is observed with serum BAFF levels in PV (15, 101, 137), likely due to variations in sample sizes across studies. Rituximab (RTX), a targeting B-lymphocyte CD20 mAb, is the most common B cell-depleting therapy for bullous dermatoses. One study found that circulating BAFF levels were significantly increased after RTX treatment, which normalised upon the recovery of peripheral CD19⁺ B cells (138). Another reported higher baseline BAFF levels in patients with PV than in healthy controls, with levels rising further after 3 months of RTX treatment, suggesting a link between BAFF and PV immunopathogenesis (137). Although the B cell-depleting agent RTX is effective for patients with PV, relapses are frequent. Hebert et al. observed that most relapses occurred precisely when autoreactive B cells reappeared and BAFF serum levels increased, suggesting that relapse after RTX therapy might be attribute to a raise in circulating BAFF levels and the reappearance of autoreactive B cells (101). Taken together, the role of the BAFF system in PV remains unclear, and further studies are required to elucidate its role in PV.

Alopecia areata (AA) is a non-scarring autoimmune hair loss disorder characterized by inflammatory cell infiltration around actively growing hair follicles (20). Circulating BAFF levels are elevated in patients with AA with more than three lesions (102). This phenomenon was confirmed by a later study, which also revealed increased tissue BAFF levels in patients with AA. Furthermore, BAFF and TH17 synergistically participate in the pathogenesis of AA (104). While research on BAFF’s role in AA remains limited, its significance cannot be overlooked.

The efficacy and safety of belimumab (BLM) in systemic lupus erythematosus (SLE) were validated across multiple pivotal clinical trials (139–146). In phase III trials for active SLE, intravenous BLM combined with standard therapy significantly outperformed placebo in SLE Responder Index (SRI) rates at week 52 in the BLISS-76 and BLISS-SC trials (141, 142). Subcutaneous administration further improved outcomes in moderate-to-severe SLE, with an SRI-4 response rate of 61.4% vs 48.4% and a 49% reduction in severe flare risk (143). Notably, hypocomplementemic/anti-dsDNA⁺ patients exhibited enhanced benefits alongside corticosteroid-sparing effects (144). Long-term extension data confirmed sustained efficacy over 7 years: SRI response increased from 41.9% (year 1) to 75.6% (year 7), with 31.4% mean prednisone reduction and 83.2% CD20⁺ B cell depletion, while maintaining stable safety profiles (145). In LN management, BLM combined with standard therapy significantly improved primary and complete renal responses, reducing renal-related event/death risk by 49% (146). These findings led to FDA approval for SLE in 2011 and an expanded indication for active LN in 2020, cementing BLM as a key LN therapy (146, 172).

The use of BLM in patients with sjögren’s syndrome (SS) has also been assessed. In a clinical study, there was a significant improvement in clinical manifestations and biomarkers of B cell activation in patients with SS who were treated long-term with BLM (23, 147). Furthermore, a clinical study assessed the safety and efficacy of BLM in patients with SSc who received background mycophenolate mofetil. This study found a significantly improvement of clinical symptoms in the BLM group compared with the placebo group (22). Overall, the results are encouraging and justify further randomised controlled studies with larger populations.

The use of BLM after rituximab (RTX) for the treatment of SLE with bullous pemphigoid (BP) has also been reported. For example, one patient with SLE overlapping with BP achieved significant clinical remission and steroid sparing after RTX-BLM sequential treatment, suggesting that a combination therapy of anti-CD20 and anti-BAFF mAbs might maintain longer B cell depletion and clinical remission (172). In addition, a case of pemphigus vulgaris (PV) was successfully treated with BLM after a failed steroid therapy course. After four cycles of BLM treatment, clinical symptoms and autoantibody levels were significantly decreased in the patient, highlighting the effectiveness of BLM in treating PV (173).

Ianalumab (VAY736), a fully human anti-B cell-activating factor receptor (BAFFR) mAb, has two action mechanisms: direct depletion of BAFFR⁺ B cells and competitive BAFFR blockade, leading to B cell apoptosis (149). In a clinical study, ianalumab was used as a single-dose treatment for patients with sjögren’s syndrome. The results showed that ianalumab reduced clinical manifestations, B cell activation biomarker expression, and serum Ig light chain levels and augmented the salivary flow rate in sjögren’s syndrome (148). Moreover, a dose-finding study confirmed a dose-related decrease in disease activity (149). However, Novartis terminated a clinical trial of VAY736 in patients with pemphigus vulgaris prior to its completion for strategic reasons (152, 174).

Despite the demonstrated efficacy of rituximab (RTX) in autoimmune diseases therapy, frequent relapses remain a clinical challenge. Several studies have investigated this issue, revealing that serum B cell-activating factor (BAFF) levels rise significantly during B cell depletion post-RTX and return to baseline upon B cell recovery. Given that excessive BAFF has been shown to rescue self-reactive B cells from apoptosis, these findings suggest that the recovery of self-reactive B cells may be attributed to elevated BAFF levels following B cell depletion (178, 179). These findings led to investigations of sequential therapy with RTX followed by belimumab (BLM). For instance, a multicentre randomised trial in patients with refractory lupus nephritis demonstrated that adding BLM to RTX/cyclophosphamide therapy was safe and modulated B cell reconstitution more effectively than B cell depletion alone (166). However, the phase III BLISS-BELIEVE trial found that sequential subcutaneous BLM with a single RTX cycle did not achieve superior disease control at week 52 or clinical remission at week 64 compared to BLM plus placebo. Nonetheless, this combination significantly reduced anti-dsDNA antibodies, modulated B cell subsets, and prolonged disease control duration, warranting further investigation (167, 168). In sjögren’s syndrome (SS), sequential RTX-BLM therapy improved clinical outcomes compared to monotherapies without compromising safety (170, 180). Collectively, although current studies on sequential therapy are limited, these findings highlight its potential as a promising therapeutic strategy that warrants further research to explore its long-term effects and mechanisms.

Emerging BAFF-targeted therapies for systemic lupus erythematosus (SLE), SS, and systemic sclerosis show translational promise in understudied autoimmune diseases. In bullous pemphigoid (BP), elevated BAFF molecule levels in memory B cells and post-RTX surges correlate with relapse, while DPP4 inhibitor-associated cases exhibit reduced BAFF molecule levels, implicating pathogenic heterogeneity (134, 135). Dual BAFF/APRIL inhibitors and SLE-validated B cell maturation antigen chimeric antigen receptor T cell immunotherapy therapies may counteract BP autoantibody pathology. For pemphigus vulgaris, post-RTX BAFF resurgence aligns with B cell recovery (101, 137, 138); sequential use of RTX-BLM or transmembrane activator and calcium modulator and cyclophilin ligand interactor agonists could limit autoreactivity. In alopecia areata, BAFF elevation is linked to Th17 inflammation (104), supporting the potential for telitacicept or JAK/BAFF dual inhibition. Disease-specific trials are critical to refine BAFF-axis modulation strategies across autoimmune diseases.