BLyS and APRIL have the capability to bind to B cells within the body, allowing these cells to evade elimination when they should naturally be removed. While BLyS primarily plays a role in B cell development and maturation, APRIL is linked to B cell activation and the secretion of antibodies. Thus, in theory, inhibiting BLyS or APRIL could diminish the population of aberrant B cells that contribute to SLE and reduce disease activity in patients. Telitacicept functions by binding to and neutralizing the activities of both BLyS and APRIL, thus hindering the maturation and survival of plasma cells and fully developed B cells. The design of telitacicept is distinctive; it is not a monoclonal antibody but a TACI-Fc fusion protein generated through recombinant DNA technology. This fusion involves merging gene segments of the TACI protein, which can target BLyS/APRIL simultaneously, with the Fc gene segment of the human IgG protein. The TACI-Fc fusion protein exhibits the combined characteristics of both proteins. Currently utilized for autoimmune disease treatment, telitacicept is undergoing clinical investigations globally to assess its efficacy in managing various autoimmune conditions. This review consolidates information on the mechanistic actions, dosing regimens, pharmacokinetics, efficacy, and safety profile of telitacicept-a dual-targeted biological agent. It integrates findings from prior experiments and pharmacokinetic analyses in the treatment of RA and SLE, striving to offer a comprehensive overview of telitacicept\'s research advancements.

UNASSIGNED: High serum levels of B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) have been observed in patients with idiopathic membranous nephropathy (iMN); however, their relationships with disease severity and progression remain unclear.
UNASSIGNED: Patients with iMN diagnosed via renal biopsy were enrolled in this study. The concentrations of BAFF and APRIL were determined using ELISA kits. Proteinuria remission, including complete remission (CR) and partial remission (PR), and renal function deterioration were defined as clinical events. The Cox proportional hazards method was used to analyze the relationship between cytokine levels and disease progression.
UNASSIGNED: Seventy iMN patients were enrolled in this study, with a median follow-up time of 24 months (range 6-72 months). The serum levels of BAFF and APRIL were higher in iMN patients than in healthy controls but lower than those in minimal change disease (MCD) patients. The serum BAFF level was positively correlated with the serum APRIL level, serum anti-phospholipase A2 receptor (anti-PLA2R) antibody level, and 24-h proteinuria and negatively correlated with the serum albumin (ALB) level. However, no significant correlation was observed between the serum APRIL level and clinical parameters. According to the multivariate Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), immunosuppressive agent use, 24-h proteinuria, APRIL level, and anti-PLA2R antibody, only the serum BAFF level was identified as an independent predictor of PR (HR, 0.613; 95% CI, 0.405-0.927; p = 0.021) and CR of proteinuria (HR, 0.362; 95% CI, 0.202-0.648; p < 0.001).
UNASSIGNED: A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.

Heart failure remains a global threaten to public health, cardiac fibrosis being a crucial event during the development and progression of heart failure. Reportedly, M2 macrophages might affect endothelial cell (ECs) and fibroblast proliferation and functions through paracrine signaling, participating in myocardial fibrosis. In this study, differentially expressed paracrine factors between M0/1 and M2 macrophages were analyzed and the expression of TNFSF13 was most significant in M2 macrophages. Culture medium (CM) of M2 (M2 CM) coculture to ECs and cardiac fibroblasts (CFbs) significantly promoted the cell proliferation of ECs and CFbs, respectively, and elevated α-smooth muscle actin (α-SMA), collagen I, and vimentin levels within both cell lines; moreover, M2 CM-induced changes in ECs and CFbs were partially abolished by TNFSF13 knockdown in M2 macrophages. Lastly, the NF-κB and Akt signaling pathways were proved to participate in TNFSF13-mediated M2 CM effects on ECs and CFbs. In conclusion, TNFSF13, a paracrine factor upregulated in M2 macrophages, could mediate the promotive effects of M2 CM on EC and CFb proliferation and fibrogenic alterations.

UNASSIGNED: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Proliferation-inducing ligand (APRIL) was identified as an important cause of glycosylation deficiency of IgA1 (Gd-IgA1), which can \'trigger\' IgAN. Our previous study indicated that high migration group protein B2 (HMGB2) in peripheral blood mononuclear cells from patients with IgAN was associated with disease severity, but the underlying mechanism remains unclear.
UNASSIGNED: The location of HMGB2 was identified by immunofluorescence. qRT-PCR and Western blotting were used to measure HMGB2, HMGA1, and APRIL expression. Gd-IgA1 levels were detected by enzyme-linked immunosorbent assay (ELISA). In addition, we used DNA pull-down, protein profiling, and transcription factor prediction software to identify proteins bound to the promoter region of the APRIL gene. RNA interference and coimmunoprecipitation (Co-IP) were used to verify the relationships among HMGB2, high mobility group AT-hook protein 1 (HMGA1), and APRIL.
UNASSIGNED: HMGB2 expression was greater in IgAN patients than in HCs and was positively associated with APRIL expression in B cells. DNA pull-down and protein profiling revealed that HMGB2 and HMGA1 bound to the promoter region of the APRIL gene. The expression levels of HMGA1, APRIL, and Gd-IgA1 were downregulated after HMGB2 knockdown. Co-IP indicated that HMGB2 binds to HMGA1. The Gd-IgA1 concentration in the supernatant was reduced after HMGA1 knockdown. HMGA1 binding sites were predicted in the promoter region of the APRIL gene.
UNASSIGNED: HMGB2 expression is greater in IgAN patients than in healthy controls; it promotes APRIL expression by interacting with HMGA1, thereby inducing Gd-IgA1 overexpression and leading to IgAN.

Intestinal infections are strongly associated with infant mortality, and intestinal immunoglobulin A (IgA) is important to protect infants from intestinal infections after weaning. This study aims to screen probiotics that can promote the production of intestinal IgA after weaning and further explore their potential mechanisms of action. In this study, probiotics promoting intestinal IgA production were screened in weanling mouse models. The results showed that oral administration of Bifidobacterium bifidum (B. bifidum) FL228.1 and Bifidobacterium bifidum (B. bifidum) FL276.1 significantly enhanced IgA levels in the small intestine and upregulated the expression of a proliferation-inducing ligand (APRIL) and its upstream regulatory factor toll-like receptor 4 (TLR4). Furthermore, B. bifidum FL228.1 upregulated the relative abundance of Lactobacillus, while B. bifidum FL276.1 increased the relative abundance of Marvinbryantia and decreased Mucispirillum, further elevating intestinal IgA levels. In summary, B. bifidum FL228.1 and B. bifidum FL276.1 can induce IgA production in the intestinal tract of weanling mice by promoting intestinal APRIL expression and mediating changes in the gut microbiota, thus playing a significant role in enhancing local intestinal immunity in infants.

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.

BACKGROUND: Early diagnosis of vitreoretinal lymphoma (VRL) is critical for the successful treatment of this rare intraocular malignancy. However, fast and reliable diagnosis of VRL in patients presenting with intermediate or posterior non-infectious uveitis remains a challenge. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are vital factors in the pathophysiology, diagnosis, and prognosis of primary central nervous system lymphoma (PCNSL) and systemic autoimmune diseases. However, their utility as biomarkers for the diagnosis of VRL and uveitis remains unclear.
METHODS: In this retrospective study, we analyzed APRIL and BAFF levels in the aqueous humor (AH) of 43 eyes of 40 patients, including 23 eyes of 20 patients with VRL, eight eyes of eight patients with uveitis, and 12 eyes of 12 patients with other ocular diseases (OODs). Additionally, we measured their levels after induction of chemotherapy in five eyes of five patients with VRL.
RESULTS: AH levels of APRIL reliably distinguished VRL from uveitis, with a specificity of 78.3% and sensitivity of 75%. BAFF also showed similar potential. Serial AH analysis of patients with VRL during chemotherapy demonstrated a corresponding decline in AH levels of APRIL and BAFF.
CONCLUSIONS: This study extends the spectrum of valuable diagnostic biomarkers for VRL and uveitis. In patients with uveitis, the assessment of AH APRIL may help accelerate the diagnosis of VRL. Moreover, our results underline the important role of APRIL and BAFF in therapeutic monitoring of VRL.

Excessive secretion of cytokines (such as APRIL and BAFF) in the bone marrow microenvironment (BMM) plays an essential role in the formation of relapsed or refractory multiple myeloma (MM). Blocking the binding of excessive cytokines to their receptors is becoming a promising approach for MM therapy. Here, we proposed a strategy of engineering cell membrane-based nanovesicles (NVs) to reconstruct B cell maturation antigen (BCMA), a receptor of APRIL and BAFF, to capture excess APRIL/BAFF in BMM as a bait protein. Our results showed that reconstructed BCMA expressed on the membrane of NVs (Re-BCMA-NVs) retained the ability of binding to soluble and surface-bound APRIL/BAFF in BMM. Consequently, Re-BCMA-NVs blocked the activation of the NF-κB pathway, downregulating the expression of anti-apoptosis genes and cell cycle-related genes, and hence inhibiting MM cell survival. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib (BTZ) in vitro and in vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy. STATEMENT OF SIGNIFICANCE: Excessive APRIL and BAFF is reported to promote the survival of MM cell and facilitate the formation of resistance to bortezomib therapy. In this study, we bioengineered cell membrane derived reconstructed BCMA nanovesicles (Re-BCMA-NVs) to capture both soluble and cell-surface APRIL and BAFF. These NVs inhibited the activation of NF-κB pathway and thus inhibit the survival of MM cells in 2D, 3D and subcutaneous mouse tumor models. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib in vitro and in vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.

Gut microbes play an important role in the development of host B cells. It has been controversial whether GALT is the development site of B cells in pigs. By investigating the relationship between gut microbes and the development of B cells in the GALT of piglets, we found, to our knowledge for the first time, that early B cells exist in the gut lamina propria (LP) in pigs at different ages. We further used Lactobacillus rhamnosus GG (LGG) to treat piglets. The results showed that LGG promotes the development of the early B lineage, affects the composition of the Ig CDR3 repertoires of B cells, and promotes the production of IgA in the intestinal LP. Additionally, we found that the p40 protein derived from LGG can activate the EGFR/AKT and NF-κB signaling pathways, inducing porcine intestinal epithelial cells (IPEC-J2) to secrete a proliferation-inducing ligand (APRIL), which promotes IgA production in B cells. Finally, we identified ARF4 and DIF3 as candidates for p40 receptors on IPEC-J2 by GST pull-down, liquid chromatography-mass spectrometry/mass spectrometry analysis, and coimmunoprecipitation. In conclusion, LGG could promote early B cell differentiation and development in the intestinal LP in piglets and might contribute to promoting IgA production via secretion of p40, which interacts with the membrane receptors on IPEC-J2 and induces them to secrete APRIL. Our study will provide insight to aid in better utilization of probiotics to increase human health.

Carotid artery lumen diameter (CALD) and carotid artery intima-media thickness (CIMT) are essential factors for estimating the risk of many cardiovascular diseases. The automatic measurement of them in ultrasound (US) images is an efficient assisting diagnostic procedure. Despite the advances, existing methods still suffer the issue of low measuring accuracy and poor prediction stability, mainly due to the following disadvantages: (1) ignore anatomical prior and prone to give anatomically inaccurate estimation; (2) require carefully designed post-processing, which may introduce more estimation errors; (3) rely on massive pixel-wise annotations during training; (4) can not estimate the uncertainty of the predictions. In this study, we propose the Anatomical Prior-guided ReInforcement Learning model (APRIL), which innovatively formulate the measurement of CALD & CIMT as an RL problem and dynamically incorporate anatomical prior (AP) into the system through a novel reward. With the guidance of AP, the designed keypoints in APRIL can avoid various anatomy impossible mis-locations, and accurately measure the CALD & CIMT based on their corresponding locations. Moreover, this formulation significantly reduces human annotation effort by only using several keypoints and can help to eliminate the extra post-processing steps. Further, we introduce an uncertainty module for measuring the prediction variance, which can guide us to adaptively rectify the estimation of those frames with considerable uncertainty. Experiments on a challenging carotid US dataset show that APRIL can achieve MAE (in pixel/mm) of 3.02±2.23 / 0.18±0.13 for CALD, and 0.96±0.70 / 0.06±0.04 for CIMT, which significantly surpass popular approaches that use more annotations.