Elevated BAFF Levels Research Articles

Serum BAFF level is associated with the presence and severity of coronary artery disease and acute myocardial infarction

ObjectiveThe 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.MethodsSerum 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.ResultsSignificantly 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.ConclusionCirculating 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.

Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case–control study includes a cohort (women, 18–60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal–Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (rs = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

BAFF rs9514828 gene polymorphism and the risk of the development of inhibitors in children with severe haemophilia A.

Haemophilia A (HA) is an x-linked recessive disease due to deficiency of coagulation factor VIII (FVIII). The development of neutralizing antibodies (inhibitors) against infused FVIII is a major concern. B cell activating factor (BAFF) has been implicated in several autoimmune diseases. We aimed to evaluate the possible association of BAFF rs9514828 gene polymorphism and the risk of the development of FVIII inhibitor in children with severe HA. This cohort study was carried out on 100 newly diagnosed boys with severe HA who were never treated before with FVIII concentrate. Assessment of serum levels of BAFF and BAFF rs9514828 genotyping at first diagnosis was performed and the patients were followed up for the completion of a total of 50 exposure days or the development of inhibitors whichever occurred first. The patients were divided as positive or negative according to the presence or absence of inhibitors. The risk allele for BAFF rs9514828 (T) was significantly more frequent in the inhibitor positive patients than the inhibitor negative patients (P=.003). In addition, CT+TT genotypes were associated with increased risk of FVIII inhibitor development. Receiver operating characteristics (ROC) analysis showed that BAFF levels could predict the development of FVIII inhibitors at a cut-off value of ≥ .92 with a sensitivity of 85.9% and a specificity of 80.2%. BAFF rs9514828 gene polymorphism could be independent risk factor and elevated BAFF levels might be useful prognostic marker for the development of FVIII inhibitor in newly diagnosed children with severe HA.

Serum cytokines in ANCA-associated vasculitis: Correlation with disease-related clinical and laboratory findings

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic, autoimmune disease. Cytokine dysregulation during active disease and clinical remission, reflects significant immunological activity in various disease stages, and might be responsible for the potential relapse of ANCA-vasculitis. ObjectivesThis study aimed to screen serological profiles in active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and to determine their associations with clinical characteristics. Materials and methodsSerum IL-10, IL-12, IL-17, IL-21, IL-23, B cell activating factor (BAFF) concentrations were determined by Quantikine HS ELISA in 71 patients, 47 with GPA and 24 with MPA, and compared with 16 healthy controls. Subsequently, the correlations between serum IL-10, IL-12, IL-17, IL-21, IL-23, BAFF levels, and both laboratory and clinical abnormalities were investigated. ResultsBAFF levels were significantly higher in GPA than MPA, and healthy controls. IL-10 and BAFF levels were elevated in GPA patients with pulmonary involvement. Higher BAFF levels might reflect severe GPA. IL-10 and IL-12 levels were higher in MPA than GPA. In MPA, IL-10 levels were highest in patients with short disease duration, and young individuals. IL-12 correlated positively with BVAS and was elevated in patients with cardiovascular involvement and nasal S. aureus carriers. ConclusionsIn MPA, IL-12 correlates positively with disease activity, and is significantly increased in patients with cardiovascular involvement and nasal S. aureus carriers. Increased IL-10 is observed in young MPA patients and in those with short MPA duration. Elevated BAFF and IL-10 levels are associated with pulmonary involvement in GPA. High BAFF levels might reflect severe GPA.

MO272CLINICOPATHOLOGICAL CORRELATION OF APRIL AND BAFF IN IG A NEPHROPATHY- A SINGLE CENTER LONGITUDINAL OBSERVATIONAL STUDY

Abstract Background and Aims Aberrantly glycosylated IgA1 molecules are important in the pathogenesis of IgA nephropathy. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines involved in immunoglobulin class switching and production of galactose deficient IgA1(Gd IgA1). We aimed to study the association of serum levels of APRIL and BAFF with the clinical severity and pathological grading of IgA nephropathy (IgAN) and to assess the strength of the association by studying the clinicopathological correlation. Method The research study was conducted as a single-center longitudinal observational study. The study subjects were recruited based on the pathological diagnosis of primary IgA nephropathy. The plasma levels of APRIL, BAFF and Gd IgA1 were estimated using enzyme-linked immunosorbent assay (ELISA). All the study subjects were followed up for one year to study the renal outcome. Results In our study group of thirty-eight patients, the median estimated glomerular filtration rate(eGFR) was 33.9(15.9,79.4) ml/minute/1.73m2. The median levels of the cytokines APRIL and BAFF were 170.81(82.45, 550.61) ng/L and 6.66(3.39,16.33) ng/ml respectively. The baseline characteristics of the study group is given in table 1. APRIL levels had significant positive correlation with Gd IgA1 levels (correlation coefficient 0.556, p=0.003) in patients with IgAN. We also observed that patients with elevated APRIL levels had elevated BAFF levels also (correlation coefficient 0.657, p &amp;lt;0.001). Patients who had crescents, mesangial hypercellularity and endocapillary proliferation in biopsy had elevated APRIL and BAFF levels whereas patients with segmental sclerosis and tubular atrophy had low levels of APRIL(Table 2). However, the levels of APRIL and BAFF did not show any significant correlation with eGFR and proteinuria at time of presentation. At the end of one year, 12(31.5%) patients reached end stage renal disease (ESRD) and these patients had lower levels of APRIL, BAFF, and Gd IgA1. It was also seen that eighty-three percent of those who reached ESRD had chronic changes in biopsy like tubular atrophy and interstitial fibrosis(p=0.05). Hence the severity of tubulointerstitial fibrosis in histology correlated well with progression to end stage renal disease as seen in most glomerular diseases. But we did not find any association between APRIL, BAFF, and Gd IgA1 levels and the decline in eGFR over one year. Conclusion We conclude that levels of APRIL and BAFF are associated with elevated levels of Gd IgA1 in patients with IgAN and had a significant association with proliferative lesions in renal biopsy. But these cytokines levels did not have any association with the eGFR at time of presentation nor decline in eGFR over one year.

Serum cytokines in ANCA-associated vasculitis: Correlation with disease-related clinical and laboratory findings

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic, autoimmune disease. Cytokine dysregulation during active disease and clinical remission, reflects significant immunological activity in various disease stages, and might be responsible for the potential relapse of ANCA-vasculitis. ObjectivesThis study aimed to screen serological profiles in active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and to determine their associations with clinical characteristics. Materials and methodsSerum IL-10, IL-12, IL-17, IL-21, IL-23, B cell activating factor (BAFF) concentrations were determined by Quantikine HS ELISA in 71 patients, 47 with GPA and 24 with MPA, and compared with 16 healthy controls. Subsequently, the correlations between serum IL-10, IL-12, IL-17, IL-21, IL-23, BAFF levels, and both laboratory and clinical abnormalities were investigated. ResultsBAFF levels were significantly higher in GPA than MPA, and healthy controls. IL-10 and BAFF levels were elevated in GPA patients with pulmonary involvement. Higher BAFF levels might reflect severe GPA. IL-10 and IL-12 levels were higher in MPA than GPA. In MPA, IL-10 levels were highest in patients with short disease duration, and young individuals. IL-12 correlated positively with BVAS and was elevated in patients with cardiovascular involvement and nasal S. aureus carriers. ConclusionsIn MPA, IL-12 correlates positively with disease activity, and is significantly increased in patients with cardiovascular involvement and nasal S. aureus carriers. Increased IL-10 is observed in young MPA patients and in those with short MPA duration. Elevated BAFF and IL-10 levels are associated with pulmonary involvement in GPA. High BAFF levels might reflect severe GPA.

P1617RENAL TRANSPLANT PATIENTS HARBOR NEUTROPHILS SECRETING B-CELL ACTIVATING FACTOR (BAFF) WHICH CAN BE SUPPRESSED BY MTOR INHIBITORS

Abstract Background and Aims B cell activating factor (BAFF) is a cytokine which drives B cell survival and maturation. Several studies have shown that elevated BAFF levels in renal transplant patients are associated with increased risk for the development of donor specific antibodies and antibody mediated rejection. It was the aim of this study to investigate neutrophils as cellular source of BAFF in renal transplant patients. Method Neutrophils (NT) were freshly isolated from whole blood of healthy controls (HC) and renal transplant patients (RTX). After isolation, purity of neutrophils was usually above 98%. Neutrophils were stimulated with LPS or TNFα in presence of Granulocyte-colony stimulating factor (GCSF) or Granulocyte macrophage colony-stimulating factor (GMCSF). In selected conditions, FK506 or rapamycin was added. Supernatants were harvested after 20 hours of culture and BAFF levels were determined by ELISA. Results GCSF/TNFα and GCSF/LPS were the most potent stimuli leading to BAFF secretion of NT in HC (403 ±64 pg/ml and 421 ±69 pg/ml). NT derived RTX showed similar capacity to secrete BAFF as compared to HC (GCSF/TNFα: 515 ±31 pg/ml and GCSF/LPS: 539.4 ±36 pg/ml). Treatment of cultures with rapamycin reduced BAFF levels (515 ±100 pg/ml vs. 348 ±27 pg/ml, p&amp;lt;0.001). Treatment with FK506 was less efficacious (515 ±31 pg/ml vs. 465 ±31 pg/ml, p=0.01). Conclusion NT may enhance of B cell maturation and survival via BAFF. BAFF-secretion by NT can be suppressed with mTOR inhibitors. In renal transplantation, NT might promote formation of allo-antibodies and drive antibody mediated rejection.

B Cell-Activating Factor Is Associated with Testosterone and Smoking Status in Non-Ambulatory Men with Chronic Spinal Cord Injury.

B cell-mediated autoimmunity may contribute to poor neurological outcomes after spinal cord injury (SCI). B cell-activating factor (BAFF) is a key cytokine involved in B cell development, proliferation, activation, and survival whose expression is elevated in men with chronic SCI. The aim of this study was to assess factors associated with circulating BAFF in non-ambulatory males with chronic SCI. We assessed the association between clinical and demographic factors, health habits, and circulating BAFF levels in a convenience sample of 43 non-ambulatory men with chronic spinal cord injury (≥ 1 year post-injury). Serum BAFF and total testosterone levels were quantified by enzyme-linked immunosorbent assay. Body composition was determined by whole body dual-energy X-ray absorptiometry. In multivariable models, active smokers had significantly greater BAFF levels than former/nonsmokers (871 pg/mL vs. 665 pg/ml, p = 0.002). BAFF decreased 36 ± 11.1 pg/mL for every 1 ng/mL increase in total testosterone (p = 0.002). This model explained 41% of the variation in circulating BAFF levels (model p < 0.0001). Our findings suggest that modifiable health habits may be associated with elevated BAFF levels in men with non-ambulatory chronic SCI. Further, the significant and independent negative association between testosterone levels and BAFF would suggest a link between androgen deficiency and autoimmunity observed in SCI via modulation of BAFF and B cell numbers. This points toward BAFF as a potential biomarker of injury severity and a target of therapies designed to reduce neuroinflammation and improve neurological outcomes after SCI.

Depletion of BAFF cytokine exacerbates infection in Pseudomonas aeruginosa infected mice

BackgroundCystic fibrosis (CF) is a genetic disease characterized by chronic inflammation of the lungs that is ineffective at clearing pathogens. B-cell activating factor (BAFF), a cytokine involved in the development of B-cells, is known to be elevated in CF patients with subclinical infections. We postulate that the elevated BAFF levels in CF patients might be triggered by Pseudomonas aeruginosa infection and it might play a protective role in the regulation of lung responses to infection. MethodsTo address this hypothesis, we used a well characterized model of CFTR.KO mice infected with a clinical strain of P. aeruginosa (PA508). We quantified cell types with flow cytometry, concentration of cytokines by ELISA tests, bacterial load by colony counting and lung physiology by metacholine-induced lung resistance. ResultsOur data demonstrates that BAFF is not elevated in uninfected CF mice, and infection with Pseudomonas leads to significant induction of this regulatory cytokine. We also demonstrate that the maintenance of BAFF levels and its induction during the infection is important for clearance of Pseudomonas infection as its depletion during the course of infection leads to decrease in the resolution of infection both in WT and CFTR-KO mice. Interestingly, the depletion of BAFF not only results in a depletion of B cells numbers but also to a significant decrease in the number of regulatory T cells in the non-infected lungs. ConclusionsOverall, our data demonstrate for the first time that BAFF is an important regulatory molecule helping to maintain the immunological response to infection and clearance of lung infection.

Associations of B cell-activating factor (BAFF) and anti-BAFF autoantibodies with disease activity in multi-ethnic Asian systemic lupus erythematosus patients in Singapore.

To measure the levels of B cell-activating factor (BAFF) and endogenous anti-BAFF autoantibodies in a cohort of multi-ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age- and sex-matched healthy controls were assayed for BAFF and anti-BAFF immunoglobulin (Ig)G antibody levels by enzyme-linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti-BAFF-IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti-BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM-R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti-dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM-R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti-BAFF IgG, which were correlated negatively with disease activity (r=-0·436, P < 0·01), levels of anti-dsDNA antibody (r=-0·347, P<0·02) and BAFF (r=-0·459, P<0·01). The majority of patients in this multi-ethnic Asian SLE cohort had elevated levels of BAFF and anti-BAFF antibodies. Anti-BAFF autoantibody levels correlated negatively with clinical disease activity, anti-dsDNA and BAFF levels, suggesting that they may be disease-modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti-cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti-cytokine therapies.

Sjogren's syndrome: Review of the aetiology, Pathophysiology & Potential therapeutic interventions.

BackgroundSjogren’s syndrome (SS) is an autoimmune disorder characterised by lymphocytic infiltration of exocrine glands, resulting in glandular dysfunction. Objectives: This study aims to review the aetiology of Sjogren’s syndrome, highlight aspects that contribute to the pathophysiology of the disease and explore treatment options that target different mediators of pathogenesis.Material and MethodsThe MEDLINE/PubMed and Google Scholar databases were searched systematically with the terms “Sjogren’s syndrome”; “clinical”; “treatment”; “management”. Eligible studies had to meet a predefined inclusion criteria.Results912 identified studies were evaluated against the inclusion criteria. 25 eligible studies were included for review. Sjogren’s syndrome is a multifactorial condition with genetic, environmental and hormonal factors playing a role in establishing the condition. B-cell activating factor (BAFF) is an important mediator in the induction and perpetuation of this condition. Elevated BAFF levels, found in patients with SS, promote growth of B-cells and subsequent production of autoantibody; anti-SSA/Ro. BAFF inhibitors are important potential therapeutic drugs that may be effective in patients with Sjogren’s syndrome. Other potential targets include CD20 and CD22 that cause B-cell depletion.ConclusionsThe pathophysiology of this exocrinopathy has not fully been elucidated. Potential therapeutic interventions include BAFF inhibitors and anti-CD20 and anti-CD22 therapy. However, no clinical trials have been conducted on subjects with Sjogren’s syndrome to support existing research. Key words:Sjogren’s syndrome, autoimmune, rheumatology.

Serum BAFF levels, Methypredsinolone therapy, Epstein-Barr Virus and Mycobacterium avium subsp. paratuberculosis infection in Multiple Sclerosis patients.

Elevated B lymphocyte activating factor BAFF levels have been reported in multiple sclerosis (MS) patients; moreover, disease-modifying treatments (DMT) have shown to influence blood BAFF levels in MS patients, although the significance of these changes is still controversial. In addition, BAFF levels were reported increased during infectious diseases. In our study, we wanted to investigate on the serum BAFF concentrations correlated to the antibody response against Mycobacterium avium subspecies paratuberculosis (MAP), Epstein-Barr virus (EBV) and their human homologous epitopes in MS and in patients affected with other neurological diseases (OND), divided in Inflammatory Neurological Diseases (IND), Non Inflammatory Neurological Diseases (NIND) and Undetermined Neurological Diseases (UND), in comparison to healthy controls (HCs). Our results confirmed a statistically significant high BAFF levels in MS and IND patients in comparison to HCs but not NIND and UND patients. Interestingly, BAFF levels were inversely proportional to antibodies level against EBV and MAP peptides and the BAFF levels significantly decreased in MS patients after methylprednisolone therapy. These results implicate that lower circulating BAFF concentrations were present in MS patients with humoral response against MAP and EBV. In conclusion MS patients with no IgGs against EBV and MAP may support the hypothesis that elevated blood BAFF levels could be associated with a more stable disease.

Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome

Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-β and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Investigating the role of BAFF in different mouse models of allergic asthma

Introduction: The cytokine B cell activating factor of the TNF family (BAFF) is crucial for the homeostatic development, differentiation and proliferation of B cells in the periphery. It is well known that elevated BAFF levels are associated with autoimmune diseases but its role in allergic diseases including asthma is barely understood.

B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways

AbstractRecent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.

Elevated BAFF Levels in the Cerebrospinal Fluid of Patients with Neuro‐Behçet’s Disease: BAFF is Correlated with Progressive Dementia and Psychosis

Neuro-Behçet's disease (NBD) is a serious complication of Behçet's disease. Generally, NBD patients with a chronic course are refractory to immunosuppressive treatment, resulting in the deterioration of personality. In this study, levels of B cell-activating factor belonging to the TNF family (BAFF) were measured in the cerebrospinal fluid (CSF) from 18 patients with NBD, 27 patients with epidemic aseptic meningitis (AM), 24 patients with multiple sclerosis (MS) and 34 healthy controls. BAFF levels in patients with NBD were significantly elevated compared with healthy controls, but showed no statistically significant elevation compared with either of the disease controls. In contrast, CSF IL-6 levels were slightly elevated in patients with NBD and significantly elevated in patients with AM and MS compared with healthy controls. Patients with NBD were subdivided into two groups according to their clinical course (eight patients with a slowly progressive course presenting with psychosis and dementia and 10 patients with an acute course including aseptic meningitis, brainstem involvement and myelopathy). BAFF levels were significantly increased in those with a slowly progressive course compared with those with an acute course. CSF BAFF levels did not correlate with serum BAFF levels, CSF cell counts or CSF IL-6 levels in patients with NBD. These data suggested that BAFF was produced within the central nervous system and may be associated with the development of NBD, particularly with a progressive course.

Elevated serum levels of B-cell activating factor in pediatric renal transplant patients

B-cells are increasingly recognized as important players in alloimmunity. B cell-activating factor (BAFF) and its receptor BAFF-R are essential for B-cell differentiation and survival. Data on BAFF levels in pediatric renal transplant (RT) patients are scarce. It is known from adult data that elevated BAFF levels correlate with an unfavorable outcome in bone marrow and kidney recipients. To analyze this hypothesis in pediatric renal transplant patients we performed a cross-sectional analysis of serum BAFF levels, lymphocyte surface BAFF-R expression, and clinical variables in a cohort of 43 pediatric renal transplant patients. We studied serum BAFF, CD19+ B-, and FoxP3+ regulatory T-cells (Tregs) and BAFF-R expression in 43 children 2.9 (0.1-12.4) years after RT on maintenance immunosuppression. Twenty-two healthy children and 19 children with chronic kidney disease stage 5 (CKD5) served as controls. BAFF levels were significantly higher in RT patients than in healthy children (1,435±574 vs 894±189 pg/mL; p<0.0001) whereas numbers of B-cells and Tregs were significantly lower. BAFF-R expression on B-cells was decreased after RT (531±334 vs 707±257 MFI; p<0.005), BAFF inversely correlated with BAFF-R (r=-0.5022, p<0.006), but not with B-cell count. BAFF was elevated in CKD5 patients (1,276±294 pg/mL). In RT patients BAFF was significantly higher in those with eGFR <60 ml/min/1.73m(2) (1,553±447 vs 1,234±323 pg/mL; p=0.02). BAFF levels and BAFF-R expression did not correlate with HLA antibody status, time after transplantation, age or gender of the patients. Serum BAFF concentrations were significantly elevated in pediatric RT patients. They correlated with decreased BAFF-R expression on CD19+ B-cells and impaired allograft function. Our findings of a dysregulated BAFF/BAFF-R axis may be of clinical relevance after renal transplantation and therefore underline the importance of further research into BAFF-dependent mechanisms.

A BAFF-R Mutation Associated with Non-Hodgkin Lymphoma Exhibits Altered TRAF Binding and Reveals New Insights Into Proximal BAFF-R Signaling

AbstractAbstract 468The requirement for BAFF and BAFF-R in normal human and murine B cells is well studied, but there is also significant evidence to suggest that BAFF plays an important role in malignant B cell proliferation and survival. Serum BAFF levels are elevated in patients with non-Hodgkin lymphoma (NHL) and high BAFF levels correlate with aggressive disease and a poor response to therapy. There is also increasing genetic evidence suggesting an association between the development of human disease and genetic variation in genes encoding BAFF and its receptors. Mutations in TNFRSF13B (TACI) were identified in patients with familial common variable immunodeficiency (CVID) and IgA deficiency and we have found that single nucleotide polymorphisms (SNP) in TNFSF13B (BAFF) are associated with elevated BAFF levels and risk for developing NHL. To build upon these findings we sequenced BAFF and its receptors; TNFSF13B, TNFRSF13B, TNFRSF17(BCMA), and TNFRSF13C (BAFF-R) in NHL patients to identify novel genetic variants that may be associated with NHL risk. Among 40 individual samples (20 controls and 20 follicular lymphoma (FL) cases) that were bi-directionally sequenced we identified a heterozygous cytosine to thymidine transition in 1 patient specimen at position 475 (C475T) of TNFRSF13C. The C475T transition encodes a missense substitution of tyrosine for histidine in codon 159 (H159Y) in the highly conserved cytoplasmic tail of BAFF-R, adjacent to the TRAF3 binding motif PVPAT. We next expanded our analysis of BAFF-R H159Y and analyzed NHL tumor biopsies for the presence of the mutation. 4/41 (10%) follicular lymphomas (FL), 2/42 (5%) diffuse large B cell lymphomas, 1/22 (5%) lymphoplasmacytic lymphomas (LPL), and 1/24 (4%) mucosal associate lymphoid tissue lymphomas carried the heterozygous mutation. The BAFF-R H159Y mutation was not detected in any of the normal control DNA from healthy donors (n=100). Given its close proximity to the TRAF3 binding site in the cytoplasmic domain of BAFF-R we first wanted to determine if the H159Y mutation altered BAFF induced signaling. We generated cell lines that express HA-tagged wildtype BAFF-R, BAFF-R with the H159Y mutation, or BAFF-R with an ablated TRAF3 binding site as a negative control. Analysis of cells expressing H159Y BAFF-R demonstrates that this mutation results in increased BAFF-R-mediated NFκB1 and NF-κB2 activation. The enhanced signal activated by BAFF-R H159Y is coupled with a several fold increase in TRAF3, TRAF2, and TRAF6 recruitment to BAFF-R and increased IgM production. We further demonstrate that recruitment of TRAF6 to BAFF-R is not unique to the mutant H159Y BAFF-R, but is also an important and necessary feature of BAFF-R signaling in normal B cells. Collectively, our data identify a novel lymphoma-associated mutation in BAFF-R and describe exciting new aspects of BAFF-R signaling that are important for understanding normal B cell homeostasis and function, as well as pathogenic BAFF-R contributions to human disease. Disclosures:No relevant conflicts of interest to declare.

Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients

B-cell activating factor belonging to tumour necrosis factor family (BAFF) is essential for B-cell survival and function through interaction with its receptors BAFF receptor 3 (BR3), B-cell maturation antigen (BCMA) and/or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), though BCMA and/or TACI can also bind to a proliferation-inducing ligand (APRIL). We evaluate the correlation of the expressions of these ligands/receptors with different clinical manifestations of systemic lupus erythematosus (SLE). Levels of BAFF and APRIL in plasma from 73 SLE patients were determined by enzyme-linked immunosorbent assay. Expressions of BR3, TACI and BCMA on CD19+ B cells were detected by flow cytometry. Clinical data were collected and disease activity was evaluated using SLEDAI-2000. SLE patients had elevated BAFF and APRIL levels in their plasma. BAFF levels correlated positively with SLEDAI while negatively with the BR3 protein expression on CD19+ B cells (p < .05). The detected BR3 protein expression in SLE patients was reduced on CD19+IgD+CD27-, CD19+IgD+CD27+ as well as CD19+IgD-CD27+ B cells compared to the counterparts of healthy controls (p < .001), whereas SLE patients did not differ from healthy controls in BR3 mRNA levels. In untreated new-onset patients, the expression rate of BR3 on CD19+ B cells correlated negatively with SLEDAI (p < .05). Elevation of BAFF and reduction of BR3 on CD19+ B cells were more obvious in those with lupus nephritis (LN, p < .05). TACI expression on CD19+ B cells was up-regulated only in those subjects with LN (p < .05). Elevated plasma BAFF and reduced BR3 protein expression on peripheral B cells could act as biomarkers for active disease in SLE patients. High expression of TACI may indicate the occurrence of LN.