ABSTRACT
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.
Subject(s)
Adipocytes , Autoantibodies , B-Cell Activating Factor , Immunoglobulin G , Insulin Resistance , Obesity , Phagocytosis , Animals , Insulin Resistance/immunology , B-Cell Activating Factor/metabolism , B-Cell Activating Factor/immunology , Mice , Obesity/immunology , Obesity/metabolism , Autoantibodies/immunology , Adipocytes/immunology , Adipocytes/metabolism , Phagocytosis/immunology , Immunoglobulin G/immunology , Male , Diet, High-Fat/adverse effects , Mice, Inbred C57BL , Apoptosis/immunology , Adipose Tissue, White/immunology , Adipose Tissue, White/metabolism , Macrophages/immunology , Macrophages/metabolism , Disease Models, AnimalABSTRACT
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.
Subject(s)
B-Cell Activating Factor , Disease Progression , Glomerulonephritis, Membranous , Proteinuria , Tumor Necrosis Factor Ligand Superfamily Member 13 , Humans , Glomerulonephritis, Membranous/blood , Glomerulonephritis, Membranous/diagnosis , B-Cell Activating Factor/blood , Male , Female , Middle Aged , Adult , Prognosis , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Proteinuria/blood , Proteinuria/etiology , Proportional Hazards Models , Receptors, Phospholipase A2/immunology , Receptors, Phospholipase A2/blood , Case-Control Studies , Aged , Glomerular Filtration Rate , Kidney/physiopathology , Kidney/pathologyABSTRACT
IMPACT: Immune dysregulation is thought to contribute to chronic lymphocytic leukemia (CLL) risk, but biological mechanisms are unclear. We discovered that increased serum levels of B-cell activating factor (BAFF), an important regulator of B-cell maturation, were associated with a decreased risk of CLL, even >10 years after blood draw. Our findings suggest that BAFF could be a useful biomarker to assess risk among individuals at high risk, such as those with monoclonal b-cell lymphocytosis.
Subject(s)
B-Cell Activating Factor , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , B-Cell Activating Factor/blood , Male , Female , Aged , Middle Aged , Biomarkers, Tumor/blood , Risk Factors , Aged, 80 and overABSTRACT
A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.
Subject(s)
Aging , Homeostasis , Immunoglobulin A , Mice, Inbred BALB C , Physical Conditioning, Animal , Animals , Immunoglobulin A/metabolism , Immunoglobulin A/immunology , Mice , Aging/immunology , Cytokines/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Cell Activating Factor/metabolism , B-Cell Activating Factor/genetics , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Intestine, Small/immunology , Intestine, Small/metabolism , Male , Plasma Cells/immunology , Plasma Cells/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/geneticsABSTRACT
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.
Subject(s)
B-Cell Activating Factor , B-Cell Activation Factor Receptor , B-Cell Maturation Antigen , Interleukin-6 , Transmembrane Activator and CAML Interactor Protein , Tumor Necrosis Factor Ligand Superfamily Member 13 , Animals , B-Cell Activating Factor/immunology , B-Cell Activating Factor/metabolism , B-Cell Activating Factor/genetics , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/immunology , Tumor Necrosis Factor Ligand Superfamily Member 13/genetics , B-Cell Maturation Antigen/immunology , B-Cell Maturation Antigen/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/immunology , Interleukin-6/metabolism , Interleukin-6/immunology , Mice , B-Cell Activation Factor Receptor/metabolism , B-Cell Activation Factor Receptor/immunology , B-Cell Activation Factor Receptor/genetics , Plasma Cells/immunology , Plasma Cells/metabolism , Mice, Knockout , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Mice, Inbred C57BLABSTRACT
BACKGROUND: The long-term use of rituximab (RTX) has been gaining ground in the treatment of systemic autoimmune diseases. The adverse events (AEs) associated with its use different to infections are being reported. METHODS: A cohort of patients with SAIDs treated at a high-complexity center in Cali (southwestern Colombia) with follow-up from January 2008 to December 2022 were examined to search for potential AEs associated with prolonged use of RTX. RESULTS: From 178 patients with long-term use of RTX 3 (1.68%) had lymphadenopathies with lymphoid follicular hyperplasia related to BAFF overexpression, 4 (2.24%) with bronchiectasis, and 4 (2.24%) with lymphoplasmacytic cystitis. CONCLUSION: Bronchiectasis, lymphoid follicular hyperplasia related to BAFF overexpression, and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX.
Subject(s)
Autoimmune Diseases , B-Cell Activating Factor , Bronchiectasis , Cystitis , Rheumatic Diseases , Rituximab , Humans , Rituximab/adverse effects , Rituximab/administration & dosage , Female , Male , Middle Aged , Autoimmune Diseases/chemically induced , Autoimmune Diseases/drug therapy , Bronchiectasis/drug therapy , Cystitis/chemically induced , Rheumatic Diseases/drug therapy , Adult , Antirheumatic Agents/adverse effects , Antirheumatic Agents/administration & dosage , Lymphadenopathy/chemically induced , Aged , Retrospective StudiesABSTRACT
Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children's hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.
Subject(s)
B-Cell Activating Factor , Humans , B-Cell Activating Factor/blood , Female , Male , Child , Child, Preschool , Adolescent , Proof of Concept Study , B-Lymphocytes/metabolism , B-Lymphocytes/immunology , Infant , Primary Immunodeficiency Diseases/blood , Immunity, Humoral , Case-Control Studies , Immunologic Deficiency Syndromes/bloodABSTRACT
It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.
Subject(s)
Autoimmune Diseases , B-Lymphocytes , Lymphocyte Depletion , Animals , Humans , Antigens, CD19/immunology , Antigens, CD20/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , B-Cell Activating Factor/immunology , B-Lymphocytes/immunology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/therapy , Lymphocyte Depletion/methods , Multiple Sclerosis/immunology , Multiple Sclerosis/therapyABSTRACT
The purpose of this study is to investigate the previously unknown connection that succinate has with neutrophils in the setting of adjuvant-mediated immunological enhancement. It has been discovered that succinates stimulate the recruitment of neutrophils in immunization sites, which in turn induces the expression of what is known as neutrophil-derived B cell-activating factor (BAFF). Further amplification of vaccine-induced antibody responses is provided via the succinate receptor 1-interferon regulatory factor 5 (SUCNR1-IRF5)-BAFF signaling pathway, which provides insights into a unique mechanism for immunological enhancement.NEW & NOTEWORTHY This study explores the role of succinate as a vaccine adjuvant, revealing its capacity to enhance neutrophil recruitment at immunization sites, which boosts B cell activation through the succinate receptor 1-interferon regulatory factor 5-B cell-activating factor (SUCNR1-IRF5-BAFF) signaling pathway. Results demonstrate succinate's potential to amplify vaccine-induced antibody responses, highlighting its significance in immunological enhancement and offering new insights into the adjuvant mechanisms of action, particularly in neutrophil-mediated immune responses.
Subject(s)
Adjuvants, Immunologic , Neutrophils , Signal Transduction , Succinic Acid , Neutrophils/immunology , Neutrophils/metabolism , Animals , Succinic Acid/metabolism , Adjuvants, Immunologic/pharmacology , Humans , Mice , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/drug effects , Neutrophil Infiltration/drug effects , B-Cell Activating Factor/metabolism , B-Cell Activating Factor/immunology , B-Cell Activating Factor/genetics , Mice, Inbred C57BL , FemaleABSTRACT
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.
Subject(s)
B-Cell Activating Factor , B-Cell Activation Factor Receptor , Nephritis , Transcriptome , Animals , Male , Mice , B-Cell Activating Factor/genetics , B-Cell Activating Factor/metabolism , B-Cell Activation Factor Receptor/metabolism , B-Cell Activation Factor Receptor/genetics , Disease Models, Animal , Gene Expression Profiling , Mice, Inbred C57BL , Mice, Knockout , Nephritis/metabolism , Nephritis/genetics , Nephritis/pathology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Signal TransductionABSTRACT
Cytokines from the Tumour Necrosis Factor (TNF) family are important regulators of both physiological and pathological processes. The discovery of novel TNF ligands and receptors, BAFF and APRIL, have opened up new possibilities for scientists to explore the effect of these cytokines on the human immune system. The role of BAFF/APRIL system in B lymphocytes is particularly important for survival and maintenance of homeostasis. Aberrant expression of the system is associated with various immunological disorders. Hence, this study provides a comprehensive overview of the past and present BAFF/APRIL system research development in a bibliometric perspective. To our best knowledge, this is the first ever bibliometric analysis conducted focusing on the BAFF/APRIL system. A total of 1055 relevant documents were retrieved from WoSCC. Microsoft Excel, VOSviewer, and Biblioshiny of R studio were bibliometric tools used to analyse the scientific literature. From 1999, the annual publications showed an upward trend, with Journal of Immunology being the most productive journal. USA leads the race for BAFF/APRIL system research developments. Pascal Schneider, a senior researcher affiliated with University of Lausanne, Switzerland was recognised as the most productive author and institution in the BAFF/APRIL system research field. The research focus transitioned from focusing on the role of the system in B cell biology, to immunological disorders and finally to development of BAFF/APRIL targeting drugs. Despite several studies elucidating briefly the pathway mechanism of BAFF/APRIL system in B-cell selection, substantial research on the mechanism of action in disease models and T cell activation and development of immunomodulating drugs from natural origins remains largely unexplored. Therefore, future research focusing on these areas are crucial for the deeper understanding of the system in disease manifestations and progression allowing a better treatment management for various immunological disorders.
Subject(s)
B-Cell Activating Factor , Bibliometrics , Tumor Necrosis Factor Ligand Superfamily Member 13 , Humans , B-Cell Activating Factor/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolismABSTRACT
INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.
Subject(s)
B-Cell Activating Factor , Immunologic Factors , JC Virus , Leukoencephalopathy, Progressive Multifocal , Natalizumab , Humans , Natalizumab/therapeutic use , B-Cell Activating Factor/blood , B-Cell Activating Factor/genetics , Male , Leukoencephalopathy, Progressive Multifocal/blood , Leukoencephalopathy, Progressive Multifocal/genetics , Adult , Female , Immunologic Factors/therapeutic use , JC Virus/immunology , JC Virus/genetics , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/immunology , Middle Aged , Antibodies, Viral/blood , Polymorphism, Single NucleotideABSTRACT
The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.
Subject(s)
Antiviral Agents , Cryoglobulinemia , Vasculitis , Humans , Cryoglobulinemia/drug therapy , Cryoglobulinemia/etiology , Antiviral Agents/therapeutic use , Male , Vasculitis/drug therapy , Vasculitis/virology , Middle Aged , Female , Aged , Hepacivirus/drug effects , Ribavirin/therapeutic use , Sofosbuvir/therapeutic use , Imidazoles/therapeutic use , Valine/analogs & derivatives , Valine/therapeutic use , Pyrrolidines/therapeutic use , B-Cell Activating Factor , Interferon-alpha/therapeutic use , Drug Therapy, Combination , Hepatitis C/drug therapy , Hepatitis C/complications , Hepatitis C/virology , Treatment Outcome , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/virology , CarbamatesABSTRACT
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
Subject(s)
Biomarkers , Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Humans , Female , Male , Adult , Multiple Sclerosis, Relapsing-Remitting/blood , Middle Aged , Multiple Sclerosis, Chronic Progressive/blood , Multiple Sclerosis, Chronic Progressive/diagnosis , Biomarkers/blood , Osteopontin/blood , B-Cell Activating Factor/blood , Matrix Metalloproteinase 2/blood , Cytokine Receptor gp130/blood , Young AdultABSTRACT
Peri-implantitis (PI) and periodontitis (PD) are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of PI and PD lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. PI, PD, and control patients were recruited (nâ =â 62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between PI and PD lesions in the proportions of immune cells. PI tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1ß, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A, and BAFF were higher in PI tissues, but not in PD, than in control tissues. The immune cell composition did not differ significantly between PI and PD, but an enhanced inflammatory profile was seen in PI tissue. PI lesions were enriched in B cells, and displayed increased levels of IL-1ß, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid.
Subject(s)
Gingival Crevicular Fluid , Peri-Implantitis , Periodontitis , Humans , Peri-Implantitis/immunology , Peri-Implantitis/pathology , Male , Female , Middle Aged , Periodontitis/immunology , Periodontitis/pathology , Gingival Crevicular Fluid/immunology , Interleukin-1beta/metabolism , Interleukin-1beta/analysis , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/analysis , B-Lymphocytes/immunology , Interleukin-17/metabolism , Aged , Adult , Interleukin-4/metabolism , Inflammation/immunology , Cytokines/metabolism , B-Cell Activating FactorABSTRACT
BACKGROUND: Gestational diabetes mellitus (GDM) is a prevalent condition with an unclear pathogenesis. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are potential key players in GDM. PARTICIPANTS, MATERIALS, AND METHODS: In a longitudinal observational study, we monitored women from the first trimester through 24-28 weeks of gestation, focusing on the development of GDM. Serum levels of BAFF and APRIL, as well as their mRNA expression, were evaluated in both the first and third trimesters. Furthermore, we assessed cytokines, adipokines, and placental hormones in the serum. RESULTS: In the first trimester, participants who later developed GDM exhibited elevated serum BAFF and reduced serum APRIL levels, although the mRNA expression of these molecules was similar to controls. Serum BAFF exhibited significant positive correlations with metabolic markers and placental hormones. Conversely, serum APRIL was negatively correlated with insulin resistance and inflammatory markers but positively correlated with adiponectin. In the early third trimester, GDM participants continued to display higher serum BAFF levels and lower serum APRIL levels than controls. There was no significant difference in mRNA expression of BAFF between GDM and control groups. Conversely, APRIL mRNA expression was significantly lower in the GDM group. The predictive potential of first-trimester BAFF and APRIL levels for future GDM development was explored, with both molecules demonstrating strong predictive capability. DISCUSSION AND CONCLUSION: This study suggests that elevated serum BAFF and reduced serum APRIL levels during pregnancy may be associated with the development of GDM. These biomarkers can serve as potential early predictors for GDM.
Subject(s)
B-Cell Activating Factor , Biomarkers , Diabetes, Gestational , Pregnancy Trimester, First , Tumor Necrosis Factor Ligand Superfamily Member 13 , Humans , B-Cell Activating Factor/blood , Female , Pregnancy , Diabetes, Gestational/blood , Diabetes, Gestational/diagnosis , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Tumor Necrosis Factor Ligand Superfamily Member 13/genetics , Adult , Pregnancy Trimester, First/blood , Biomarkers/blood , Longitudinal Studies , Prognosis , Follow-Up Studies , Case-Control StudiesABSTRACT
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.
Subject(s)
B-Cell Activating Factor , Interleukin-1beta , Multiple Myeloma , Neutrophils , Stromal Cells , Tumor Microenvironment , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Humans , Tumor Microenvironment/immunology , Neutrophils/immunology , Neutrophils/metabolism , Stromal Cells/metabolism , Stromal Cells/immunology , B-Cell Activating Factor/metabolism , Interleukin-1beta/metabolism , Neutrophil Activation , STAT3 Transcription Factor/metabolism , Bone Marrow/immunology , Bone Marrow/pathologyABSTRACT
B-cell activating factor (BAFF), a critical regulator of B cells, is involved in various autoimmune diseases. Inflammatory bowel disease (IBD) is a group of chronic and recurrent intestinal inflammatory disorders with unclear etiology, and its global incidence has been increasing in recent years. Abnormal immune responses triggered by multiple factors are closely related to the pathogenesis of IBD. Previous studies have confirmed the association of B-cell abnormal activation and increased production of autoantibodies with the development of ulcerative colitis. However, the involvement of BAFF in the mechanisms of IBD remains unclear. This review summarizes the potential role of BAFF in the pathogenesis of IBD and provides an overview of targeted therapies on BAFF in IBD, aiming to contribute insights for targeted treatments of IBD.
Subject(s)
B-Cell Activating Factor , Colitis, Ulcerative , Inflammatory Bowel Diseases , Humans , B-Cell Activating Factor/metabolism , B-Lymphocytes , Colitis, Ulcerative/complications , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/etiologyABSTRACT
Immune thrombocytopenia (ITP) is an autoimmune-driven disease characterized by increased destruction and impaired platelet production resulting in an enhanced risk of bleeding. Immunosuppressant agents are the most common treatment strategies for ITP. Despite their efficacy, these medications often cause unpredictable side effects. Recent investigations revealed that patients with ITP exhibit elevated B-cell activating factor (BAFF) levels in both their spleens and serum. Belimumab, a BAFF inhibitor, illustrated a promising therapeutic avenue for managing ITP by interfering with BAFF activity and long-lived plasma cell production. Both clinical and experimental studies have yielded positive outcomes when combining rituximab with an anti-BAFF monoclonal antibody in treating ITP. In addition, ianalumab, a monoclonal antibody with a dual mechanism that targets BAFF-R and deletes peripheral BAFF-R+ B cells, is currently being used for ITP treatment [NCT05885555]. The upcoming results from novel BAFF inhibitors, such as ianalumab, could offer clinicians an additional therapeutic option for treating ITP.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , B-Cell Activating Factor , Interleukin-4 , Antibodies, Monoclonal/therapeutic useABSTRACT
OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a form of SLE associated with severe NP syndromes causing mortality and morbidity. Respecting the fundamental of BAFF in NPSLE pathophysiology, we investigated its clinical value. METHODS: Totally 105 NPSLE and 101 SLE cases without NPSLE (non-NPSLE, control) were included. Serum BAFF/TNF-α/IL-6/IL-10 levels were measured using ELISA kits. T lymphocytes were detected by flow cytometry. The independent influencing factors for NPSLE, and the auxiliary diagnostic efficacy and the ability of BAFF levels to predict adverse prognosis of NPSLE patients were analyzed by multiple factor logistic regression, and ROC curve and survival curve. RESULTS: In NPSLE patients, serum BAFF level was increased and positively correlated with SLEDAI-2k, serum proinflammatory cytokines, while negatively correlated with CD4+T/CD8+T cells, and anti-inflammatory cytokine. High serum BAFF protein level was associated with a higher risk of developing NPSLE. The AUC of serum BAFF > 301.7 assisting in NPSLE diagnosis was 0.8196. Furthermore, high levels of serum BAFF were associated with a higher risk of adverse outcomes in NPSLE patients. . CONCLUSION: Serum BAFF level in NPSLE patients was correlated with lymphocytes and high serum BAFF protein level could assist in diagnosis and to predict adverse outcomes in NPSLE patients.