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B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells. Consequently, BAFF-deficient mice often show suppressed humoral responses, while BAFF-overexpressing mice show the higher number of mature B cells and may develop autoimmune-like manifestations and B-cell lymphoproliferative diseases. Elevated BAFF levels are also associated with various hematological malignancies, and its expression correlates with disease progression in some cases. Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL. Atacicept, a decoy receptor for BAFF and APRIL, showed tolerability in a phase 1b trial for CLL. Tabalumab, another monoclonal antibody targeting BAFF, did not demonstrate significant efficacy in a phase 2 study for relapsed/refractory multiple myeloma. BAFF ligand-based CAR-T cells are designed to target BAFF receptors and show promise in preclinical studies, particularly for B-cell malignancies. The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights. [ABSTRACT FROM AUTHOR]

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH. [ABSTRACT FROM AUTHOR]

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity. [ABSTRACT FROM AUTHOR]

Chronic viral infections cause thymic involution yet the potential for broader, longer‐term impact on thymic composition remains unexplored. Here we show that chronic, but not acute, lymphocytic choriomeningitis virus infection promotes a unique population of immature B cells in the thymus. We show that chronic viral infection promotes signals within the thymus, including the expression of B‐cell activating factor (BAFF), that favor the maturation of this population as these cells acquire expression of CD19 and immunoglobulin M. Mechanistically, type I interferon (IFN‐I), predominantly IFNβ, signals to thymic hematopoietic cells, strongly delaying T‐cell development at the earliest precursor stage. Furthermore, IFN‐I signaling to the nonhematopoietic compartment provides a second signal essential to favor B‐cell differentiation and maturation within the thymus. Importantly, chronic infection yields changes in the B‐cell population for at least 50 days following infection, long after thymic atrophy has subsided. Thus, the inflammatory milieu induced by chronic viral infection has a profound, and long‐lasting, effect on thymic composition leading to the generation of a novel population of thymic B cells. [ABSTRACT FROM AUTHOR]

• B-cell activating factor is essential for the modulation of immune humoral responses. • BAFF was repeatedly associated with non-psychiatric inflammatory and autoimmune conditions. • High levels of soluble BAFF characterize both acute and stabilized patients with SZ and BD and under a genetic control. • sBAFF levels are correlated with positivity of stigma of infection and of autoimmune comorbidities. • BAFF appears as a promising marker of inflammatory processes in SZ and BD. Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3′UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3′UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, we observed that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10 and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017). In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041). We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans -nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. Methods: Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. Results: Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078–1.580) and AMI (adjusted OR 2.874, 95% CI 1.708–4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841–10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score. Conclusion: Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH.

Abstract Objective The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. Methods Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. Results Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P

Introduction Systemic Lupus Erythematosus, an autoimmune disease, can target various organs of the human body. Lupus nephritis (LN) is a major complication affecting almost half of all SLE patients, with classes “III and IV” being the most aggressive. The severity and prognosis of LN can be influenced by different biomarkers, some of which are used as therapeutic targets. One such target is the B-cell activating factor (BAFF), a key figure in the pathophysiology of SLE. New add-on treatments have emerged in the treatment of LN targeting BAFF as well as other pathways. Assortment of patients to suitable treatment combinations needs more precision using guiding markers.Methods This prospective study aims to explore BAFF-expression in patients with active-proliferative LN and its possible association with the response after induction therapy. Peripheral blood mononuclear cells (PBMC) and renal tissue samples (if applicable) were collected from participants before the initiation of induction treatment. RNA was extracted, and the expression levels of BAFF-mRNA were measured using quantitative real-time polymerase chain reaction. Clinical and laboratory data, including disease activity indices and renal functions, were recorded at baseline and 6-months after the commencement of the induction treatment.Results The study included 24 patients,14 responders and 10 non-responders. At baseline, median PBMC BAFF-mRNA expression was nearly identical in responders and non-responders. Renal BAFF-expression was found to be higher in non-responders, although non-significant (p = 0.21). Contrary to PBMC BAFF expression, renal BAFF-mRNA was negatively correlated with baseline glomerular filtration rate and with the primary endpoint of response, which was reduction of proteinuria to≥50% of baseline (p = 0.07).Conclusions Renal BAFF expression could be a better representative of severity and therapeutic response than blood expression. We acknowledge that the use of BAFF expression as a predictive for early refractoriness to therapy in LN is not yet conclusive.

BAFF, a vital B cell survival and differentiation factor, has three receptors: B‐cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.Baff−/− (which harbour no BAFF) and B6.Br3−/− mice (which harbour supra‐normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3+ and CD4+ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra‐normal levels of BAFF per se do not explain the phenotypic differences between B6.Baff−/− and B6.Br3−/− mice; (2) B cells are expanded in B6.Taci−/− mice, with preferential expansion of follicular (FO) B cells at the expense of CD19+CD21−/loCD23−/lo B cells but without the preferential expansion of Foxp3+ cells observed in B6 mice bearing a Baff transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19+CD21−/loCD23−/lo B cells are lower in young B6.Bcma−/− mice, consistent with the inability of B6.Br3−/−.Taci−/− mice to recapitulate the B cell profile of B6.Baff−/− mice; and (4) percentages of Foxp3+ cells in B6.Br3−/−.Taci−/− mice are intermediate between those in B6.Br3−/− and B6.Taci−/− mice despite the B cell profile of B6.Br3−/−.Taci−/− mice strongly resembling that of B6.Br3−/− mice. Collectively, our findings point to a non‐redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility. [ABSTRACT FROM AUTHOR]

B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affectWAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in theWAT of BAFFneutralizedmice. In vitro, plasma IgG fractions from BAFF-neutralizedmice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance. [ABSTRACT FROM AUTHOR]

Allergic Rhinitis (AR), a prevalent condition in otorhinolaryngology, is mediated by Type 1 hypersensitivity through IgE, characterized by Type 2 inflammatory response and eosinophil infiltration in the nasal mucosa. Since AR disease exhibits significant heterogeneity in symptom severity, an objective assessment of AR severity may facilitate better individualized treatment. To explore the changes in peripheral blood IL-9, Th9, and BAFF levels of allergic rhinitis (AR) in patients and the clinical significance associated with it. A retrospective study selected 80 AR patients admitted from January 2022 to October 2022 as the case group, dividing them into mild and moderate-to-severe groups based on symptom scores. Concurrently, 50 patients without AR, who were treated for nasal bone fractures or underwent septoplasty, were selected as the group for comparison. Alterations in the expression levels of peripheral blood IL-9, Th9, and BAFF were analyzed and compared among the different groups. The diagnostic value of serum BAFF for the severity of AR was analyzed using the receiver operating characteristic (ROC) curve. Noticeable variations were observed in clinical variables among the three groups such as, total IgE levels, peripheral blood eosinophil count and proportion, TNSS, and VAS (P< 0.05), while no statistically significant differences were observed in other variables (P> 0.05). The comparison of IL-9, Th9, and BAFF among the three groups revealed statistically significant differences (P< 0.05). Analysis using multivariate logistic regression revealed that IL-9 (OR = 2.365), Th9 (OR = 2.186), BAFF (OR = 2.307) were influencing factors of moderate-to-severe AR (P< 0.05). The ROC curve indicated that the AUC for the diagnosis of moderate-to-severe AR by IL-9, Th9, BAFF were 0.770, 0.734, 0.761, respectively, and the combined detection AUC was 0.888, an area under the curve higher than individual testing. Changes in peripheral blood IL-9, Th9, and BAFF levels in AR patients may function as indicators to assess the level of severity in diagnostic procedures. [ABSTRACT FROM AUTHOR]

Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy represents the most prevalent cause of glomerulonephritis worldwide and may lead to renal failure in a relevant number of cases in both paediatric and adult subjects. Although their pathogenesis is still largely unclear, evidence of immune abnormalities provides the background for the use of immunosuppressive drugs, such as corticosteroids, calcineurin inhibitors, and antiproliferative and alkylating agents. Unfortunately, these treatments fail to achieve a sustained remission in a significant percentage of affected patients and are burdened by significant toxicities. Recent developments of new biologics, including anti-BAFF/APRIL inhibitors and molecules targeting complement components, offered the opportunity to selectively target immune cell subsets or activation pathways, leading to more effective and safer hypothesis-driven treatments. However, studies testing new biologic agents in IgAN should also consider paediatric populations to address the unique needs of children and close the therapeutic gap between adult and paediatric care. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection (AMR) can cause graft failure following renal transplantation. Neutrophils play a key role in AMR progression, but the exact mechanism remains unclear. We investigated the effect of neutrophils on AMR in a mouse kidney transplantation model. The mice were divided into five groups: syngeneic transplantation (Syn), allograft transplantation (Allo), and three differently treated AMR groups. The AMR mouse model was established using skin grafts to pre-sensitize recipient mice. Based on the AMR model, Ly6G-specific monoclonal antibodies were administered to deplete neutrophils (NEUT−/− + AMR) and TACI-Fc was used to block B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) signaling (TACI-Fc + AMR). Pathological changes were assessed using hematoxylin–eosin and immunohistochemical staining. Banff values were evaluated using the Banff 2015 criteria. Donor-specific antibody (DSA) levels were assessed using flow cytometry, and BAFF and APRIL concentrations were measured using ELISA. Compared to the Syn and Allo groups, a significantly increased number of neutrophils and increased C4d and IgG deposition were observed in AMR mice, accompanied by elevated DSA levels. Neutrophil depletion inhibited inflammatory cell infiltration and reduced C4d and IgG deposition. Neutrophil depletion significantly decreased DSA levels after transplantation and suppressed BAFF and APRIL concentrations, suggesting a mechanism for attenuating AMR-induced graft damage. Similar results were obtained after blockading BAFF/APRIL using a TACI-Fc fusion protein. In summary, neutrophil infiltration increased in the AMR mouse renal transplantation model. Neutrophil depletion or blockading the BAFF/APRIL signaling pathway significantly alleviated AMR and may provide better options for the clinical treatment of AMR. We established the AMR mouse model and significantly increased neutrophil infiltration was only observed in the kidney tissues of the AMR mice. Neutrophil depletion might reduce rejection in AMR mice by causing a decrease in BAFF and APRIL levels. The TACI-Fc fusion protein alleviated kidney injury after transplantation in AMR mice by reducing BAFF and APRIL concentrations. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19+ CD5+ B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5+ mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear. Methods: We generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo. Results: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumorpromoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. Conclusions: Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output. [ABSTRACT FROM AUTHOR]

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B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFF-neutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.

Interstitial pneumonia with autoimmune features (IPAF) is a type of interstitial lung disease (ILD) with immune features that do not meet the diagnostic criteria for specific connective tissue diseases (CTDs). This retrospective case–control study investigated the role of serum B-cell-activating factor of the tumor necrosis factor family (BAFF) and interleukin (IL)-17 as biomarkers for IPAF. The differences in serum BAFF, IL-17, and IL-10 were compared among patients with idiopathic pulmonary fibrosis (IPF), IPAF, ILD associated with CTD (CTD-ILD), and healthy controls. The patients were treatment naïve. The correlations of BAFF with IL-10, IL-17, and pulmonary function were analyzed. The classifiable value of BAFF for IPAF was examined. The results showed that the serum levels of BAFF and IL-17 in the IPAF and CTD-ILD groups were higher than in the IPF group. High BAFF levels and high predicted diffusion capacity of the lungs for carbon monoxide (DLCO) were independent predictive factors for IPAF vs IPF. In the IPAF and CTD-ILD groups, serum BAFF levels were negatively correlated with predicted values of forced vital capacity (FVC%) and diffusing capacity of the lungs for carbon monoxide (DLCO%) and positively correlated with serum IL-17 and IL-10 levels. The cutoff value of combined BAFF and IL-17 was 0.704, and the sensitivity and specificity for classifying IPAF were 78.9 and 95.7%, respectively. In conclusion, combining serum BAFF and IL-17 as a biomarker may have classifiable value in differentiating IPAF from other forms of ILD.

We have previously shown that blood levels of B-cell Activating Factor (BAFF) rise relatively to disease progression status in the context of HIV-1 infection. Excess BAFF was concomitant with hyperglobulinemia and the deregulation of blood B-cell populations, notably with increased frequencies of a population sharing characteristics of transitional immature and marginal zone (MZ) B-cells, which we defined as marginal zone precursor-like” (MZp). In HIV-uninfected individuals, MZp present a B-cell regulatory (Breg) profile and function, which are lost in classic-progressors. Moreover, RNASeq analyses of blood MZp from classic-progressors depict a hyperactive state and signs of exhaustion, as well as an interferon signature similar to that observed in autoimmune disorders such as Systemic Lupus Erythematosus (SLE) and Sjögren Syndrome (SS), in which excess BAFF and deregulated MZ populations have also been documented. Based on the above, we hypothesize that excess BAFF may preclude the generation of HIV-1-specific IgG responses and drive polyclonal responses, including those from MZ populations, endowed with polyreactivity/autoreactivity. As such, we show that the quantity of HIV-1-specific IgG varies with disease progression status. In vitro, excess BAFF promotes polyclonal IgM and IgG responses, including those from MZp. RNASeq analyses reveal that blood MZp from classic-progressors are prone to Ig production and preferentially make usage of IGHV genes associated with some HIV broadly neutralizing antibodies (bNAbs), but also with autoantibodies, and whose impact in the battle against HIV-1 has yet to be determined.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.

• Phytogalactolipids plant-derived adjuvant for pathogenic vaccine. • Phytogalactolipids enhance specific antibody titers and affinity in mice. • Phytogalactolipids increase uptake ability and antigen presentation in APCs. • Phytogalactolipids stimulate APCs to release Activin A/BAFF for B cell activation. • Phytogalactolipids provide a new mechanism to boost immunity against bacteria. Various plant-derived compounds can activate immune responses against bacterial infections, and this property contributes to them being developed as effective and safe adjuvants for vaccines. This study evaluated the potential adjuvant effects of a galactolipid-enriched fraction generated from the medicinal plant Crassocephalum rabens (designated CRA). Heat shock protein 60 of periodontal disease pathogen Actinobacillus actinomycetemcomitans (AaHSP60) was taken as an antigen and mixed with CRA. The AaHSP60/CRA mixture was then injected intraperitoneally into the BALB/c mice. Titers and affinity of specific antibodies were measured by ELISA. Cytokine profiles in mouse serum or culture media of AaHSP60/CRA-treated splenocytes were analyzed by cytokine multiplex assay and ELISA kits. B cell differentiation and macrophage activation were determined by phenotyping. CRA dramatically enhanced specific antibody titers and induced Ig class switch, as shown by increases in the IgG2a, IgG2b, and IgG3 proportions of total Ig in mouse serum. Furthermore, CRA-induced anti-AaHSP60 antibodies had cross-reactivity to other bacterial HSP60s. Cell-based and animal results demonstrated that CRA induced the release of IL-21 and B cell activating factor (BAFF), which stimulated B cell differentiation. CRA enhanced cell proliferation, uptake ability, and antigen presentation in mouse phagocytes. CRA served as a vaccine adjuvant that enhance mouse immunity against pathogenic antigens. CRA strengthened the activation and capabilities of phagocytes and B cells. Therefore, CRA may be a promising adjuvant for bacterial vaccines including periodontal disease. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Advanced Research in Health Sciences (JARHS) / Sağlık Bilimlerinde İleri Araştırmalar Dergisi (SABİAD) is the property of Journal of Advanced Research in Health Sciences (JARHS) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: There may be an association between hyperprolactinemia and autoimmune diseases, possibly because of the immunostimulatory effect of prolactin. The aim of this study was to investigate the prevalence of thyroid and non-thyroid autoimmune diseases, serum B-cell activating factor (BAFF), and proliferation-inducing ligand (APRIL) levels as indicators of increased autoimmunity, quality of life, depression, and anxiety in patients with prolactinoma. Methods: Fifty-six premenopausal women with prolactinoma and 50 healthy premenopausal women were included in the study. Autoimmune markers, including anti-nuclear antibody, rheumatoid factor immunoglobulin M (IgM) (RF-IgM), anti-double-stranded DNA (anti-dsDNA), anti-transglutaminase IgA (anti TG-IgA), and anti-Sjogren's syndrome A (anti-ssA), serum BAFF, APRIL and vitamin B12 levels, thyroid function tests, anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin and thyroid Doppler ultrasound, were evaluated. Short-form 36, Beck Depression Inventory, and Beck Anxiety Inventory tests were also used. Results: The prevalence of autoimmune thyroiditis (AIT) was 32.1% in the patient group, whereas the prevalence of newly diagnosed AIT was similar to controls (p>0.05). Vitamin B12 deficiency was higher in patients with prolactinoma than in controls (25.6% and 9.1%, p=0.016). Autoantibody positivity was found to be similar between the groups (35.7% and 28.1%, p=0.25). Serum BAFF and APRIL levels were not different in patients with prolactinoma than in controls (p>0.05). Quality of life, anxiety, and depression scores were not different between patients with or without AIT and those with or without positivity for any autoantibody (p>0.05). Conclusion: One-third of the patients were diagnosed with AIT and onefourth of the patients had vitamin B12 deficiency in our study. However, non-thyroid autoimmune diseases did not increase and no alterations were detected in serum BAFF/APRIL levels in patients with prolactinoma. [ABSTRACT FROM AUTHOR]

Abstract Background Multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after the original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia, and activation of T cells with elevated IFN-γ. Observing the production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II, and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19. Results We documented a significant elevation of IFN-γ, but not IFN-α and IFN-λ in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the pre-IVIG presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients. Conclusions Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF. Graphical Abstract

Abstract Multiple sclerosis (MS) has traditionally been viewed as a chronic inflammatory disease affecting the white matter of the central nervous system. However, over the past two decades, increasing evidence has highlighted the role of gray matter pathology in MS-related disability. Numerous studies have linked the presence of leptomeningeal inflammation to a more severe disease course, underscoring its potential importance as a driver of gray matter pathology in MS. The major components of leptomeningeal inflammation include T cells, B cells, macrophages, follicular dendritic cells, and plasma cells. Since BAFF [B cell-activating factor of the tumor necrosis factor (TNF) family] promotes B cell survival and maturation and is a co-stimulator of T cells, we used anti-BAFF antibody 10F4 as a BAFF antagonist to study its effect on meningeal inflammation and adjacent brain regions in a relapsing–remitting PLP-EAE (rr-EAE) model of multiple sclerosis in SJL/J mice. rr-EAE mice were treated either with anti-BAFF antibody 10F4 or with IgG control antibody. We performed ultra-high field (11.7 T) MRI to identify areas of meningeal inflammation and track them over time in both treatment groups. We also performed histopathological analysis in brain sections of these mice to study the effects of the BAFF antagonist on leptomeningeal inflammation, and hippocampal and cortical neurons and synapses. We observed that BAFF antagonist treatment reduced B cells, T cells, and myeloid cells in regions of meningeal inflammation. Additionally, we noted that BAFF treatment protected against EAE-induced synaptic and neuronal loss in the adjacent cortex and in the CA1, CA3, and dentate gyrus regions of the hippocampus likely due to its effects on meningeal inflammation.

Abstract IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and up to 40% of patients with IgAN develop end-stage renal disease (ESRD). At present, an increasing amount of evidence indicates that the pathogenesis of IgAN is related to autoimmunity. In recent years, several studies have shown that B cell activating factors (BAFF), also known as B lymphocyte stimulators (BLyS), and proliferation-inducing ligand APRIL are extremely important for the activation of autoimmune signalling pathways, which have become key targets for the treatment of IgAN. As a dual-target biological agent, telitacicept can inhibit both BLyS and APRIL cytokines, improve the function of renal immune complexes, and reduce haematuria and proteinuria, which play important roles in IgAN pathogenesis and long-term prognosis. This article reviews the role of telitacicept in IgA nephropathy and discusses its potential for use in the treatment of IgAN and other autoimmune diseases where pathogenesis is driven by B cells.

IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and is one of the most common causes of end-stage kidney disease (ESKD) worldwide. The immunopathogenic mechanism underlying IgAN is poorly identified. Currently, the mainstay treatment of IgAN is centered on the optimization of blood pressure and a reduction in proteinuria, using an angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs). According to KDIGO, patients who persistently remain at a high risk of progressive ESKD, despite maximal supportive care, are candidates for glucocorticoid therapy. Recent discoveries regarding the pathogenesis of this disease have led to the testing of new therapeutic drugs targeting, in particular, the excessive mucosal immune reaction and the resulting systemic response as well as the complement activation and the following kidney damage and fibrosis. In this review, we examine the various therapeutic approaches to this intriguing disease.

BackgroundChronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19+ CD5+ B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5+ mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear.MethodsWe generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo.ResultsOur findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo.ConclusionsOur study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.

Multiple sclerosis (MS) has traditionally been viewed as a chronic inflammatory disease affecting the white matter of the central nervous system. However, over the past two decades, increasing evidence has highlighted the role of gray matter pathology in MS-related disability. Numerous studies have linked the presence of leptomeningeal inflammation to a more severe disease course, underscoring its potential importance as a driver of gray matter pathology in MS. The major components of leptomeningeal inflammation include T cells, B cells, macrophages, follicular dendritic cells, and plasma cells. Since BAFF [B cell-activating factor of the tumor necrosis factor (TNF) family] promotes B cell survival and maturation and is a co-stimulator of T cells, we used anti-BAFF antibody 10F4 as a BAFF antagonist to study its effect on meningeal inflammation and adjacent brain regions in a relapsing–remitting PLP-EAE (rr-EAE) model of multiple sclerosis in SJL/J mice. rr-EAE mice were treated either with anti-BAFF antibody 10F4 or with IgG control antibody. We performed ultra-high field (11.7 T) MRI to identify areas of meningeal inflammation and track them over time in both treatment groups. We also performed histopathological analysis in brain sections of these mice to study the effects of the BAFF antagonist on leptomeningeal inflammation, and hippocampal and cortical neurons and synapses. We observed that BAFF antagonist treatment reduced B cells, T cells, and myeloid cells in regions of meningeal inflammation. Additionally, we noted that BAFF treatment protected against EAE-induced synaptic and neuronal loss in the adjacent cortex and in the CA1, CA3, and dentate gyrus regions of the hippocampus likely due to its effects on meningeal inflammation. [ABSTRACT FROM AUTHOR]

A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate that APRIL inhibition can reduce proteinuria and slow the rate of kidney disease progression by acting at an upstream level in IgAN pathogenesis. In this review, we examine what is known about the physiologic roles of APRIL and evaluate the experimental and epidemiological evidence describing how these normal biologic processes are thought to be subverted in IgAN. The weight of the preclinical, clinical, and genetic data supporting a key role for APRIL in IgAN has galvanized pharmacologic research, and several anti-APRIL drug candidates have now entered clinical development for IgAN. Herein, we present an overview of the clinical results to date. Finally, we explore where more research and evidence are needed to transform potential therapies into clinical benefits for patients with IgAN. [ABSTRACT FROM AUTHOR]

Background: Multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after the original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia, and activation of T cells with elevated IFN-γ. Observing the production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II, and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19. Results: We documented a significant elevation of IFN-γ, but not IFN-α and IFN-λ in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the pre-IVIG presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients. Conclusions: Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF. [ABSTRACT FROM AUTHOR]

Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110–0.2300) vs. 0.0000 (0.0000–0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125–17.9400) vs. 0.0000 (0.0000–0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response. [ABSTRACT FROM AUTHOR]

Although various studies have been performed on the function of polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN‐MDSCs in the pathogenesis of RA and its specific mechanisms. We detected the frequencies and counts of PMN‐MDSCs, TNF‐α+ B cells and Ki67+ B cells in spleen and inflamed joints of collagen‐induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN‐MDSCs was examined by anti‐Ly6G neutralizing antibodies against PMN‐MDSCs or adoptive transfer of PMN‐MDSCs. And the modulation of PMN‐MDSCs on B cells was conducted by coculture assays, RNA‐Seq, RT‐qPCR, and so on. The mechanism of BAFF regulating B cells was verified through western blot and flow cytometry. PMN‐MDSCs accumulated in the spleen and joints of CIA mice. PMN‐MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF‐α secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN‐MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF‐α expression, proliferation and apoptosis of B cells in vitro. What's more, BAFF promoted phosphorylation of BTK/NF‐κB signalling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF‐α expression of B cells. Our study suggested that PMN‐MDSCs enhanced disease severity of CIA and manipulated TNF‐α expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF‐α expression through BTK/NF‐κB signalling pathway, which demonstrated a novel pathogenesis of PMN‐MDSCs in CIA. [ABSTRACT FROM AUTHOR]

Copyright of Saudi Medical Journal is the property of Saudi Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Viral double-stranded RNA (dsRNA) interacts with Retinoic-acid-inducible-gene-1 (RIG-1)-like receptors (RLRs) to induce type 1 interferons. Melanoma-derived-antigen-5 (MDA-5), an RLR, but not RIG-1, is found in chickens. Ducks express both RIG-1 and MDA-5, a possible cause of differences in susceptibility to influenza virus infection between chickens and ducks. Using the HD11 chicken macrophage cell line and an RT2 Profiler PCR-array system, we showed that high-molecular-weight poly(I:C), HMW-poly(I:C), upregulates CCL4, interferon-gamma, interleukin-1, and interleukin-6 mRNA transcripts. HMW-poly(I:C), an in vitro surrogate of long dsRNA species, also induces the upregulation of IL-12B and B cell activating factor (BAFF). Conversely, low-molecular-weight poly(I:C), LMW-poly(I:C) did not induce a distinct cytokine expression pattern. Nonetheless, co-transfection of LMW and HMW-poly(I:C) significantly reduced the upregulation of IL12B and BAFF by HMW-poly(I:C). These findings support previous studies that found no expression of RIG-1, a receptor for short dsRNA species, in chicken cells. Surprisingly, however, our data suggested that in the absence of RIG-1 in chicken macrophages, short dsRNA species may inhibit macrophage-mediated B cell development and survival by modulating the expression of BAFF without significantly reducing type 1 interferon response. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and up to 40% of patients with IgAN develop end-stage renal disease (ESRD). At present, an increasing amount of evidence indicates that the pathogenesis of IgAN is related to autoimmunity. In recent years, several studies have shown that B cell activating factors (BAFF), also known as B lymphocyte stimulators (BLyS), and proliferation-inducing ligand APRIL are extremely important for the activation of autoimmune signalling pathways, which have become key targets for the treatment of IgAN. As a dual-target biological agent, telitacicept can inhibit both BLyS and APRIL cytokines, improve the function of renal immune complexes, and reduce haematuria and proteinuria, which play important roles in IgAN pathogenesis and long-term prognosis. This article reviews the role of telitacicept in IgA nephropathy and discusses its potential for use in the treatment of IgAN and other autoimmune diseases where pathogenesis is driven by B cells. [ABSTRACT FROM AUTHOR]

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of >3.08 ng/mL and ≤3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (Ptrend < 0.05). The strongest association was observed for CCL17/TARC (Ptrend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas.

Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.

In this study, we determined if B lymphocytosis may serve as a JDM biomarker for disease activity. Children with untreated JDM were divided into two groups based on age-adjusted B cell percentage (determined through flow cytometry): 90 JDM in the normal B cell group and 45 in the high B cell group. We compared through T-testing the age, sex, ethnicity, duration of untreated disease (DUD), disease activity scores for skin (sDAS), muscle (mDAS), total (tDAS), CMAS, and neopterin between these two groups. The patients in the high B cell group had a higher tDAS (p = 0.009), mDAS (p = 0.021), and neopterin (p = 0.0365). Secondary analyses included B cell values over time and BAFF levels in matched patients with JM (juvenile myositis) and concurrent interstitial lung disease (ILD); JM alone and healthy controls Patient B cell percentage and number was significantly higher after 3–6 months of therapy and then significantly lower on completion of therapy (p =< 0.0001). The JM groups had higher BAFF levels than controls 1304 vs. 692 ng/mL (p = 0.0124). This study supports B cell lymphocytosis as a JDM disease-activity biomarker and bolsters the basis for B cell-directed therapies in JDM. [ABSTRACT FROM AUTHOR]

Mutations in the recombination activating gene 1 (RAG1) and RAG2 in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD. [ABSTRACT FROM AUTHOR]

To investigate the features of circulating B cells, their expressing receptors, serum levels of B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Blood samples from 24 patients with active AAV (a-AAV), 13 with inactive AAV (i-AAV), and 19 healthy controls (HC) were included in this study. The proportion of B cells and their expressing BAFF receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen were analyzed via flow cytometry. Serum levels of BAFF, APRIL, and interleukin (IL)-4, IL-6, IL-10, and IL-13 were also evaluated using an enzyme-linked immunosorbent assay. The proportion of plasmablasts (PB)/plasma cells (PC) and serum levels of BAFF, APRIL, IL-4, and IL-6 were significantly higher in a-AAV than in HC. Higher serum levels of BAFF, APRIL, and IL-4 were observed in i-AAV than in HC. Lower expression of BAFF-R on memory B cells and higher expression of TACI on CD19+ cells, immature B cells, and PB/PC were demonstrated in a-AAV and i-AAV than in HC. The population of memory B cells was positively associated with serum APRIL levels and BAFF-R expression in a-AAV. In conclusion, decreased expression of BAFF-R on memory B cells and increased expression of TACI on CD19+ cells, immature B cells, and PB/PC, as well as increased serum levels of BAFF and APRIL, were sustained even in the remission phase of AAV. Persistent aberrant signaling of BAFF/APRIL may contribute to disease relapse. Significantly decreased BAFF-R or increased TACI expression on B-cell subsets were observed in ANCA-associated vasculitis (AAV). Increased serum levels of BAFF and APRIL remained even in AAV remission. APRIL and BAFF-R were positively associated with memory B cell expression in active AAV. [ABSTRACT FROM AUTHOR]

IgA Nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Despite the histopathologic hallmark of mesangial IgA deposition, IgAN is a heterogenous autoimmune disease not only in terms of clinical presentation but also in long-term disease progression. The pathogenesis of the disease is complex and includes the generation of circulating IgA immune complexes with chemical and biological characteristics that favor mesangial deposition and reaction to mesangial under-glycosylated IgA1 accumulation, which leads to tissue injury with glomerulosclerosis and interstitial fibrosis. Patients with proteinuria over 1 g, hypertension, and impaired renal function at diagnosis are considered to be at high risk for disease progression and end-stage kidney disease (ESKD). Glucocorticoids have been the mainstay of treatment for these patients for years, but without long-term benefit for renal function and accompanied by several adverse events. A better understanding of the pathophysiology of IgAN in recent years has led to the development of several new therapeutic agents. In this review, we summarize the current therapeutic approach for patients with IgAN as well as all novel investigational agents. [ABSTRACT FROM AUTHOR]

IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and is one of the most common causes of end-stage kidney disease (ESKD) worldwide. The immunopathogenic mechanism underlying IgAN is poorly identified. Currently, the mainstay treatment of IgAN is centered on the optimization of blood pressure and a reduction in proteinuria, using an angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs). According to KDIGO, patients who persistently remain at a high risk of progressive ESKD, despite maximal supportive care, are candidates for glucocorticoid therapy. Recent discoveries regarding the pathogenesis of this disease have led to the testing of new therapeutic drugs targeting, in particular, the excessive mucosal immune reaction and the resulting systemic response as well as the complement activation and the following kidney damage and fibrosis. In this review, we examine the various therapeutic approaches to this intriguing disease. [ABSTRACT FROM AUTHOR]

Four species of invasive carp from Asia are currently advancing up the Mississippi River through its locks and dams. It has been hypothesized that this movement could be blocked in a selective manner by projecting sound projected into locks because carp, like all members of the Ostariophysi, have exceptional hearing. Although previous laboratory studies have shown that a broadband cyclic sound blocks ~ 80% of bighead and common carp, and that this value increases when sound is projected into an air curtain to create an ensonified bubble curtain (EBC), the effectiveness of EBCs at blocking other fishes including carps has not been addressed. To answer this question, the present study examined the responses of 10 fishes including 4 species of invasive carp (bighead, silver, grass, common), 2 native ostariophysians (channel catfish, golden shiner), and 4 native non-ostariophysians (rainbow trout, largemouth bass, bluegill sunfish, lake sturgeon) in a laboratory flume while a cyclic sound was either projected on its own or into a bubble curtain. The EBC, whose sound fields (sound pressure and particle acceleration) were more intense and sharper than sound alone, blocked all 4 carps 92–97% of the time for all 8 trials (i.e. without apparent habituation), while 5 native ostariophysian and non-ostariophysian fishes were also partially blocked 19–89%. In contrast, sound alone significantly blocked only bighead and common carp while affecting the other fishes including the carps to varying extents (− 44–7%). In conclusion, EBCs appear very well suited to block carps. [ABSTRACT FROM AUTHOR]