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Studies showing how BAFF and its closely related homologue APRIL activate their receptors and transmit growth and survival signals to B cells have shed new light on the association between BAFF and autoimmunity. This knowledge has prompted several clinical trials testing BAFF and APRIL antagonists for the treatment of autoimmune diseases and lymphomas. Key Points Studies examining the binding of B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) to their receptors have revealed additional layers of complexity. Trimeric forms of both BAFF and APRIL bind to the receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), but only multimeric forms of these ligands can signal through this receptor. Recent work has provided a more detailed roadmap of BAFF-induced survival signalling. The activation of the alternative nuclear factor-κB2 (NF-κB2) pathway and of the phosphoinositide 3-kinase–AKT1–mammalian target of rapamycin pathway, and the upregulation of expression of myeloid cell leukaemia sequence 1 (MCL1) provide a rational basis for the effects of BAFF on B cell survival and metabolic fitness. The role of BAFF is no longer restricted to B cells. BAFF is also produced by non-haematopoietic cells and affects B cells as well as T cells, macrophages and dendritic cells. The role of BAFF in B cell tolerance is not what it seems. BAFF does not markedly affect the negative selection of high-affinity self-reactive B cells but instead increases the proliferation of positively selected low-affinity self-reactive B cells. BAFF mediates a unique form of autoimmune disease, which is independent of T cell involvement but requires the activation of innate immune mechanisms such as Toll-like receptor activation. BAFF and/or APRIL inhibitors have shown some benefits in the clinic, but there are many remaining challenges and possible future options in the form of combined therapies. The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. The disease is characterized by activation and dysregulation of both the innate and the adaptive immune systems. The autoimmune response targets self-molecules including cell nuclei, double stranded DNA and other intra and extracellular structures. Multiple susceptibility genes within the immune system have been identified, as well as disturbances in different immune pathways. SLE may affect different organs and organ systems, and organ involvement is diverse among individuals. A universal understanding of pathophysiological mechanism of the disease, as well as directed therapies, are still missing. Cytokines are immunomodulating molecules produced by cells of the immune system. Interferons (IFNs) are a broad group of cytokines, primarily produced by the innate immune system. The IFN system has been observed to be dysregulated in SLE, and therefore IFNs have been extensively studied with a hope to understand the disease mechanisms and identify novel targeted therapies. In several autoimmune diseases identification and subsequent blockade of specific cytokines has led to successful therapies, for example tumor necrosis factor-alpha (TNF-α) inhibition in rheumatoid arthritis. Authors of this review have sought corresponding developments in SLE. In the current review, we cover the actual knowledge on IFNs and other studied cytokines as biomarkers and treatment targets in SLE.

The survival of antibody-secreting plasma cells is essential for long-lasting humoral immunity. BCMA is proposed to promote APRIL-mediated survival signals. However, extensive shedding of murine BCMA raises doubts about its role as a signaling receptor. To unequivocally establish BCMA’s function in plasma cell survival, we generate two BCMA-deficient mouse lines and examine antigen-specific plasma cells post-immunization. Contrary to previous reports, both BCMA-deficient mouse lines have comparable numbers of antigen-specific long-lived plasma cells following both protein and mRNA immunizations. Transcriptome analysis reveals no reduction in survival signaling upon BCMA deletion. Interestingly, BCMA-deficient mice show increased total plasma cell numbers in the bone marrow and mesenteric lymph nodes after boost immunizations. These results indicate that BCMA has no intrinsic role in maintaining long-lived plasma cells. Instead, we propose that BCMA’s function is limited to acting as a soluble decoy receptor for APRIL, thereby fine-tuning the plasma cell population size by limiting survival factor availability. Our findings thus provide a strong argument against the APRIL-BCMA axis being a central mechanism for plasma cell longevity. B cell maturation antigen (BCMA) has long been viewed as essential for plasma cell survival via APRIL-mediated signalling. Here, using two independent BCMA-deficient mouse models, the authors show that both the generation and long-term maintenance of plasma cells are unaffected by BCMA deficiency, and these plasma cells express normal levels of survival genes, thereby overturning the prevailing paradigm of the APRIL–BCMA axis as critical for plasma cell longevity.

The cellular components of the plasma cell niche in the bone marrow have remained elusive. Berek and co-workers show that eosinophils are key providers of plasma cell survival factors in the bone marrow. Plasma cells are of crucial importance for long-term immune protection. It is thought that long-lived plasma cells survive in specialized niches in the bone marrow. Here we demonstrate that bone marrow eosinophils localized together with plasma cells and were the key providers of plasma cell survival factors. In vitro , eosinophils supported the survival of plasma cells by secreting the proliferation-inducing ligand APRIL and interleukin-6 (IL-6). In eosinophil-deficient mice, plasma cell numbers were much lower in the bone marrow both at steady state and after immunization. Reconstitution experiments showed that eosinophils were crucial for the retention of plasma cells in the bone marrow. Moreover, depletion of eosinophils induced apoptosis in long-lived bone marrow plasma cells. Our findings demonstrate that the long-term maintenance of plasma cells in the bone marrow requires eosinophils.

Autoimmunity arises when the immune system erroneously attacks self-antigens, potentially resulting in organ dysfunction. This review focuses on the proliferation-inducing ligand, APRIL, and its critical role in regulating antibody-producing B cells. We explore the implications of APRIL in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome. Emerging evidence indicates that APRIL may modulate autoimmune pathology and influence B cell survival, particularly through its interactions with receptors like B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI). We emphasize the contrasting roles of APRIL and BAFF in autoimmunity, highlighting the conflicting data regarding their contributions to disease progression and activity levels. Furthermore, we evaluate therapeutic strategies aimed at inhibiting APRIL and compare them with existing B-cell-targeted therapies, such as rituximab and belimumab. The potential benefits of specific APRIL antagonism are discussed, especially for patients with antibody-driven autoimmune disorders. This highlights the necessity for further research into APRIL-targeted therapies in clinical practice. Ultimately, this review seeks to provide a comprehensive overview of the current understanding of APRIL’s role in autoimmunity and outline future directions for targeting this ligand in the treatment of autoimmune diseases.

Objectives To dissect the role of toll-like receptor (TLR) signalling and B cell survival/proliferating factors in the crosstalk between rheumatoid arthritis synovial fibroblasts (RASF) and B cells. Methods RASF, rheumatoid arthritis dermal fibroblasts (RADF) and osteoarthritis synovial fibroblasts (OASF) were analysed for the expression of B cell survival/proliferating factors BAFF and APRIL in resting conditions and upon stimulation with TLR2/TLR3/TLR4 ligands. Unswitched IgD+ B cells were co-cultured with RASF/OASF/RADF in the presence/absence of TLR ligands and with/without BAFF/APRIL blocking antibodies. Activation-induced cytidine deaminase (AID) mRNA expression, Iγ-Cμ and Iα-Cμ circular transcripts (CTs; markers of ongoing class-switching to IgG and IgA) and IgM/A/G production were measured to assess functional activation of B cells. Results TLR3 and to a lesser extent TLR4, but not TLR2 stimulation, induced up to ∼1000-fold BAFF mRNA and increased soluble BAFF release. APRIL was less significantly regulated by TLR3. Resting and TLR3-stimulated RASF released higher levels of BAFF/APRIL compared with RADF. TLR3 stimulation of RASF but not RADF in co-culture with B cells strongly enhanced AID expression, Iγ-Cμ and Iα-Cμ CTs and class-switching to IgG/IgA. Blockade of BAFF/APRIL signalling completely inhibited TLR3-induced, RASF-dependent expression of AID, CTs and the secretion of IgG/IgA. Conclusions RASF produce high levels of BAFF and APRIL constitutively and in response to TLR3 stimulation. These factors are critical in directly modulating AID expression, class-switch recombination and IgG/IgA production in IgD+ B cells. Overall, this work highlights a novel and fundamental role for the TLR3/B cell survival factor axis in sustaining B cell activation in the rheumatoid arthritis synovium.

Lupus nephritis (LN) is a frequent and serious complication of systemic lupus erythemosus (SLE). Both innate and adaptive immunity play essential roles in the initiation and progression of LN. B-lymphocyte stimulator (BLYS) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis factor superfamily, bind to receptors such as B-cell activating factor receptor 3 (BR3), transmembrane activator and CAML interactor protein (TACI), and B-cell maturation antigen (BCMA). BLYS and APRIL are often overexpressed in LN, showing a positive correlation with disease activity. Therapeutic targeting of BLYS/APRIL has demonstrated efficacy in reducing LN activity. Traditional immunosuppressants often have multiple contraindications and side effects due to their broad immune-suppressing effects. Recently, B-cell-targeting agents, including rituximab, belimumab, as well as telitacicept have shown promising efficacy and reduced side effects in LN treatment. Telitacicept, a novel biological agent, has been approved firstly effective for SLE treatment in China. This review focus on the role of BLYS and APRIL in LN development and progression, alongside clinical data on the targeted therapies of above biologicals.

This study aimed to investigate the expression condition of a proliferation-inducing ligand (APRIL) in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma. Fifteen patients with IgG4-ROD, 3 with MALT lymphoma, and 1 with elevated IgG4 with lacrimal gland lesions, treated in West China Hospital of Sichuan University from April 2022 to November 2023, were included. Immunofluorescence staining was used to detect the expression of APRIL in the specimen of lacrimal gland. The average expression level of APRIL in patients with lacrimal gland lesions of IgG4-ROD and MALT lymphoma were 8471.12 pixels/HPF and 2950.78 pixels/HPF respectively. The positive rates of APRIL were 10.49% and 7.23% respectively. CD138 and APRIL were colocalized, and the positive rate of their colocalization was 8.83%, and the positive areas of colocalization coincidence was 946.84 pixels/HPF in patients with IgG4-ROD. CD20 and APRIL were colocalized, and the positive rate of their colocalization was 7.04%, and the positive areas of colocalization coincidence was 949.78 pixels/HPF in patients with MALT lymphoma. We also found that the expression level and the positive rate of APRIL were positively correlated with the level of serum IgG4 in IgG4-ROD patients (r=0.5820, =0.029; r= 0.6261, =0.017; respectively). In addition, the positive rate and the positive areas of CD138 and APRIL colocalization were also positively correlated with serum IgG4 level (r=0.6420, =0.013; r= 0.5673, =0.034; respectively). APRIL is highly expressed in lacrimal gland lesions of patients with IgG4-ROD and MALT lymphoma. This overexpression may facilitate the enrichment of CD138 plasma cells and is associated with elevated serum IgG4 levels in patients with IgG4-ROD. Additionally, it may promote the proliferation of CD20 B lymphocytes in patients with MALT lymphoma.APRIL may play a certain role in the possible transformation of IgG4-ROD into MALT lymphoma.

Alloantibody represents a significant barrier in kidney transplant through the sensitization of patients prior to transplant through antibody mediated rejection (ABMR). APRIL BLyS are critical survival factors for mature B lymphocytes plasma cells, the primary source of alloantibody. We examined the effect of APRIL/BLyS blockade via TACI-Ig (Transmembrane activator calcium modulator cyclophilin lig interactor-Immunoglobulin) in a preclinical rodent model as treatment for both desensitization ABMR. Lewis rats were sensitized with Brown Norway (BN) blood for 21 days. Following sensitization, animals were then sacrificed or romized into kidney transplant (G4, sensitized transplant control); desensitization with TACI-Ig followed by kidney transplant (G5, sensitized + pre-transplant TACI-Ig); kidney transplant with post-transplant TACI-Ig for 21 days (G6, sensitized + post-transplant TACI-Ig); desensitization with TACI-Ig followed by kidney transplant post-transplant TACI-Ig for 21 days (G7, sensitized + pre- post-transplant TACI-Ig). Animals were sacrificed on day 21 post-transplant tissues were analyzed using flow cytometry, IHC, ELISPOT, RT-PCR. Sensitized animals treated with APRIL/BLyS blockade demonstrated a significant decrease in marginal zone non-switched B lymphocyte populations (p<0.01). Antibody secreting cells were also significantly reduced in the sensitized APRIL/BLyS blockade treated group. Post-transplant APRIL/BLyS blockade treated animals were found to have significantly less C4d deposition less ABMR as defined by Banff classification when compared to groups receiving APRIL/BLyS blockade before transplant or both before after transplant (p<0.0001). The finding of worse ABMR in groups receiving APRIL/BLyS blockade before both before after transplant may indicate that B lymphocyte depletion in this setting also resulted in regulatory lymphocyte depletion resulting in a worse rejection. Data presented here demonstrates that the targeting of APRIL BLyS can significantly deplete mature B lymphocytes, antibody secreting cells, effectively decrease ABMR when given post-transplant in a sensitized animal model.

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.