Serum BAFF Levels Research Articles

Ligands and receptors of the TNF superfamily are decreased in major depression and during early antidepressant therapy

BackgroundThe up-regulation of pro-inflammatory agents, amongst them tumor necrosis factor (TNF), may represent low-grade inflammation in major depression. To further elucidate inflammatory mechanisms related to TNF in depression, the aim of the current study was to investigate the involvement of ligands and receptors of the TNF/TNF-receptor-superfamily yet un- or little explored in major depression. MethodsSerum levels of ligands (TNF, TNF-related weak inducer of apoptosis [TWEAK], B-cell activating factor [BAFF], tumor necrosis factor superfamily member 14 [TNFSF14; LIGHT], A proliferation-inducing ligand [APRIL]) and receptor molecules (TNF receptor superfamily member 8 [TNFRSF8; sCD30], soluble TNF receptor type 1 [sTNFR1] and type 2 [sTNFR2]) of the TNF/TNF-receptor-superfamily were measured in 50 unmedicated patients suffering from major depression and 48 healthy controls and were reassessed in 37 of the depressed patients two weeks after the initiation of antidepressive treatment. ResultsIn comparison to the healthy controls, the interrelated serum levels of TWEAK, BAFF, TNFSF8, sTNFR1 and sTNFR2 were reduced both in the unmedicated and medicated depressed patients. Serum levels of BAFF and TNF significantly increased during the initiation of antidepressive treatment. In the combined sample of unmedicated depressed and healthy controls, but not the separate groups, scores of the BDI-II inversely correlated with levels of TWEAK, BAFF, sTNFR1, sTNFR2 and TNFSF8. ConclusionThe current findings give evidence for a role of the TNF/TNF-receptor-superfamily in the pathophysiology of major depression that may involve reduced tissue regeneration and neurogenesis rather than an acceleration of pro-inflammatory pathways.

The predictive value of CSF multiple assay in multiple sclerosis: A single center experience

BackgroundMultiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, neurodegenerative disorder. Many studies are investigating the potential role of body fluid biomarkers as prognostic factors for early identification of patients presenting with clinical isolated syndrome (CIS) at high risk for conversion to MS or to recognize RRMS patients at high risk for progression. ObjectivesTo evaluate the correlation between levels of BAFF, chitinase 3-like 1 (CHI3L1), sCD163, Osteopontin (OPN), both on serum and cerebral spinal fluid (CSF), and the disease activity and progression. We also want to explore a possible relationship between serological and CSF biomarker's levels. Patients and methodsWe enrolled 82 patients between June 2014 and June 2016. Seventy-one received a diagnosis of demyelinating disease of CNS (46 RRMS and 25 CIS), while 11 were affected by other neurological diseases. All patients underwent a neural axis MRI, lumbar puncture and blood samples. Levels of BAFF, CHI3L1, sCD163, OPN on serum and CSF were analyzed by Luminex xMAP system, with a kit 11-plex ad hoc. ResultsThe CSF CHI3L1, sCD163 and OPN levels were significantly higher in MS patients than in controls. We did not find significant differences in serum CHI3L1, sCD163 and OPN levels, nor CSF or serum BAFF levels between patient and control groups.We found significantly higher CSF level of sCD163 and CHI3L1 in all patients’ subgroups compared with controls, while OPN was higher in CIS and RR subgroups. We did not find significant differences for serum and CSF levels of all the markers between patients with or without clinical or radiological disease activity.CSF sCD163 and CHI3L1 levels was significant higher in CIS patients who converted to MS (p < 0.05).Using ROC curve analysis, CSF sCD163 resulted the best predictive factor. CSF CHI3L1 and OPN levels resulted useful independent predictors too. Combined ROCs of those three analytes demonstrated a better predictive value, with sCD163 and CHI3L1 resulting as the best combination. ConclusionsCSF sCD163 CHI3L1 and OPN levels were higher in MS patients whereas serum CHI3L1, sCD163 and OPN levels did not show differences compared with controls. This finding confirms the high CSF specificity with regards to the analysis of processes, inflammatory and non-inflammatory, that occur within the CNS.

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.

B-Cell Activating Factor Predicts Acute Rejection Risk in Kidney Transplant Recipients: A 6-Month Follow-Up Study.

B cell activating factor (BAFF) belonging to TNF family is a cytokine that enhances B-cell proliferation and differentiation. Recently, It has been suggested that BAFF might be a potential therapeutic target for treating autoimmune disease. However, the relationship between BAFF and allograft rejection is controversial, and the clinical significance of BAFF in predicting allograft rejection need to be further explored. We conducted 6-month follow-up study to confirm the hypothesis that BAFF might be a risk factor for predicting acute rejection in kidney transplant recipients. At the end of the study, a total of 155 kidney transplant recipients were recruited from October 2015 to October 2017, and classified into acute rejection group (n = 34) and stable renal function group (n = 121) according to their clinical course. We demonstrate that the serum BAFF levels when acute rejection occurred was significantly higher than that in the stable renal function group (2426.19 ± 892.19 vs. 988.17 ± 485.63 pg/mL, P < 0.05). BAFF expression was significantly enhanced in the membrane and cytoplasm of renal tubule epithelial cells in the transplant kidney tissue with acute rejection, and a positive correlation between BAFF and C4d expression was also observed (r = 0.880, P = 0.001). ROC analyses highlight the superiority of serum BAFF level before transplant over those on other post-transplant days in prediction of acute rejection episodes. The sensitivity, specificity and AUC (area under curve) were 83.3, 89.5, and 0.886%, respectively. Kaplan-Meier survival analysis showed that recipients with higher pretransplant BAFF levels had higher acute rejection incidence (P = 0.003). In conclusion, we have identified that BAFF levels are associated with the acute rejection and could be a promising biomarker to predict kidney transplant rejection risks.

B cell activation factor (BAFF) induces inflammation in the human fallopian tube leading to tubal pregnancy

BackgroundTubal pregnancy is recognized as one of the most common ectopic pregnancy types. Salpingitis may result in tubal pregnancy by causing fallopian tube occlusion and hydrosalpinx. B cell activation factor (BAFF) is a proinflammatory cytokine that helps regulate both innate and adaptive immune responses. Our previous study firstly showed that BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells, and both BAFF protein and mRNA in human inflamed fallopian tubes had higher expression levels than those in normal fallopian tubes. This study aimed to elucidate the association between the expression of BAFF gene and the inflammation in the human fallopian tube leading to tubal pregnancy.MethodsWe examined 70 patients undergoing salpingectomy for salpingitis (n = 35) and tubal pregnancy (n = 35). Twenty patients with benign uterine diseases undergoing complete hysterectomy and salpingectomy were recruited into control group. BAFF mRNA and protein in tissue samples were detected by qPCR and Western blotting methods. Furthermore, serum levels of BAFF, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured using ELISA kits.ResultsWe found statistically significantly elevated expressions of BAFF mRNA or protein in whole tissue samples, and serum levels of BAFF, TNF-α and IL-6 in whole blood samples from patients with salpingitis and tubal pregnancy, in comparison to the control group.ConclusionBased on the results, high expression of BAFF gene might induce inflammation in the human fallopian tube, suggesting its possible role in the tubal pregnancy process.

Efficacy of BAFF in Monitoring Treatment Response in Early Vietnamese Systemic Sclerosis Patients.

BACKGROUND:B-cell activating factor (BAFF) is considered to have a role in the pathogenesis of systemic sclerosis (SSc).AIM:We conducted a longitudinal study on early SSc patients to determine the change in BAFF serum level after treatment and its association with organ involvements.METHODS:A total of 46 patients (32 diffuse, 14 limited) were recruited, among which 35 patients (24 diffuse, 11 limited) completed 12-month follow-up.RESULTS:Higher pretreatment BAFF levels were observed in patients with positive anti-topoisomerase antibody (ATA) (2252.1 ± 899.7 pg/ml versus 1475.5 ± 697.6 pg/ml in ATA-negative patients; p = 0.01) and muscular involvement (2741.9 ± 1039.9 pg/ml versus 1897.2 ± 762.9 pg/ml in patients without muscular involvement; p = 0.005). Lower levels were observed in patients with interstitial lung disease (ILD) (1926.7 ± 757.9 pg/ml versus 2721.6 ± 1131.4 pg/ml in non-ILD patients; p = 0.01). After treatment, BAFF level reduced significantly in diffuse SSc patients (1652.2 ± 892.7 pg/ml versus 2147.6 ± 945.5 pg/ml before treatment; p = 0.03).CONCLUSION:Patients with worsening outcome had the highest pretreatment BAFF level and was associated with increased BAFF level after treatment. BAFF can be used to predict and monitor patients’ response to therapy.

Elevated level of B-cell-activating factor in tissues and serum of patients with vitiligo: a proof of autoimmune theory

Background Several studies strongly supported the involvement of autoimmunity in vitiligo pathogenesis, which proposed the alteration of both humoral and cellular immunity leading to the destruction of melanocytes. B-lymphocyte-activating factor (BAFF) is a member of tumor necrosis factor family that has an important role in peripheral B-cell survival and homeostasis. The increased production of BAFF may lead to autoimmunity. Objective To assess BAFF levels in both serum and tissue in patients with vitiligo to detect its possible role in the disease. Patients and methods The present case–control study included 30 patients with vitiligo and 30 age-matched and sex-matched healthy controls. Overall, 5 ml of blood sample was retrieved, and lesional skin biopsy specimen was obtained from the margin of lesional skin from each patient and site-matched control for estimation of BAFF levels by ELISA. Results A higher level of BAFF was detected in tissues and sera of patients with vitiligo (8.3±5.0 and 1.9±1.0, respectively) compared with healthy controls (1.0±0.3 and 1.1±0.5 with P<0.001 and <0.005, respectively). Significant correlation was found between BAFF levels in either tissue or serum with duration of the disease (r=0.9, P<0.001 and r=0.7, P<0.001, respectively). Moreover, significant correlation was found between BAFF in tissue and BAFF in serum (r=0.7 and P<0.001). Conclusion The present study provides further evidence on the role of BAFF in the pathogenesis of vitiligo.

Serum B cell activating factor and interleukin 10 levels in common variable immunodeficiency: Relationship with clinical findings

Background/Aim. Common variable immunodeficiency (CVID) is an immunologically and clinically heterogeneous disorder. Disturbed cytokine production is implicated in dysfunctional immune response. The aim of this study was to investigated B-cell activating factor (BAFF) and interleukin (IL)- 10 levels in CVID patients. Methods. The study included 28 CVID patients diagnosed and followed during a 20-year period (mean follow-up 14.5 years). Control groups consisted of 4 patients with X-linked agammaglobulinemia (XLA) and 21 healthy subjects. According to clinical characteristics, the CVID patients were divided into four groups which partly overlap: chronic pulmonary diseases (n = 21), splenomegaly (n = 13), autoimmune diseases (n = 9) and patients with recurrent infections despite regular intravenous immunoglobulin (IVIg) substitution (n = 4). The serum levels of BAFF and IL-10 were measured by commercial ELISA. Results. The BAFF levels were found to be higher in all CVID patients compared to the healthy controls (p &lt; 0.01). The most significant differences were observed in the patients with pulmonary diseases and splenomegaly (p &lt; 0.0001). Also, concentrations of IL-10 were higher in all CVID patients in comparison with the XLA patients (p &lt; 0.05) and healthy subjects (p &lt; 0.01). A statistically significant positive correlation (r = 0.86; p &lt; 0.01) was found between the levels of BAFF and IL-10 in the CVID patients with autoimmune diseases. We demonstrated that the CVID patients with chronic pulmonary diseases had higher levels of IL-10, while the CVID patients with recurrent infections had higher BAFF concentrations in comparison to the patients without these features (p &lt; 0.05). Conclusion. In spite of the limited number of patients, this is the first report from Serbia, examining the serum levels of BAFF and IL-10 in the CVID patients. Our study showed significantly increased concentrations of serum BAFF and IL-10 in the patients with CVID compared to the healthy subjects. Further studies are needed to confirm our findings that the BAFF levels are more pronounced in patients with recurrent infections while IL-10 levels are higher in patients with chronic pulmonary diseases.

BAFF-R and TACI expression on CD3+ T cells: Interplay among BAFF, APRIL and T helper cytokines profile in systemic lupus erythematosus

BackgroundSystemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease, characterized by loss of immune tolerance against self-antigens where autoantibody production is the hallmark of disease. B-cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines that promote autoreactive cell survival, immunoglobulin-class switching and autoantibody responses in human and mouse SLE models. BAFF and APRIL exert their functions through interactions with their receptors BAFF-R and TACI that are differentially expressed in B lymphocyte subsets, monocytes, dendritic cells and T lymphocytes. BAFF stimulation favors T lymphocyte activation and cytokine production through BAFF-R, which could contribute to the Th1, Th17 and/or Th2 response dysregulation observed in SLE patients. ObjectiveTo evaluate the expression of the cytokines BAFF and APRIL and their association with the receptors BAFF-R and TACI on CD3+ T cells and to evaluate Th1/Th2/Th17 cytokine profile in patients with SLE. MethodsFifteen healthy controls (HC) and 36 SLE patients were included, and their demographic and clinical data were assessed. The disease activity index (Mex-SLEDAI) and damage index (SLICC) were applied to the SLE patients. BAFF-R and TACI expression on CD3+ T cells were evaluated by flow cytometry. Serum BAFF and APRIL concentrations were measured by enzyme-linked immunosorbent assays (ELISA). Cytokine levels of Th1 (IL-12, IL-2, IFN-γ, TNF-α), Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-1β e IL-17) were quantified with a multiplex assay (MAGPIX). Statistical analysis was performed using PASW Statistics v.20 and GraphPad Prism v.6 software. ResultsNo differences in BAFF-R or TACI expression on the CD3+ T cells of SLE and HC were observed. BAFF-R expression correlates inversely with disease activity (r = −0.538, p < 0.01), while TACI correlates with disease activity (r = 0.530, p < 0.05). Serum BAFF and APRIL levels were high in SLE patients and correlated with the disease activity index Mex-SLEDAI (r = 0.621, p < 0.01 and r = 0.416, p < 0.05). SLE patients were found to have significantly higher levels of IL-12, IFN-γ, TNF-α, IL-6, IL-10, IL-13, IL-1β and IL-17 compared to HC (p < 0.05). Cytokines IL-17 (r = 0.526) and TNF-α (r = 0.410) correlate with disease activity (p < 0.05), while APRIL (r = 0.477), IL-10 (r = 0.426) and IFN-γ (r = 0.440) levels were associated with organ damage (p < 0.01). Serum BAFF expression levels correlate with IL-4 (r = 0.424; p < 0.05), IL-6 (r = 0.420; p < 0.05) and IL-10 (r = 0.459; p < 0.01), whereas APRIL levels correlate with IL-2 (r = 0.666; p < 0.01), IL-12 (r = 0.611; p < 0.01) and TNF-α (r = 0.471; p < 0.05) cytokines. A subgroup of SLE patients with high serum BAFF levels (>2 ng/mL) also showed increased APRIL, IL-2, IL-6 and IL-10 levels (p < 0.05). Finally, BAFF, IL-4 and TNF-α serum levels were associated with high titers of antinuclear antibodies. ConclusionsThe study demonstrates an imbalance in the Th1/Th2 cytokine profile, with increased proinflammatory cytokines, as well as BAFF and APRIL serum levels. Associations of BAFF with Th2 profile cytokines and disease activity, as well as APRIL with Th1 profile cytokines and organ damage, suggest that BAFF and APRIL generated in the autoimmunity context could through still unknown mechanisms, modulate the microenvironment, and perpetuate the inflammatory response, autoantibody production and organ damage observed in SLE patients.

Prognostic Significance of Serum BAFF, APRIL, TACI and BCMA Levels in Chronic Lymphocytic Leukemia.

As chronic lymphocytic leukemia (CLL) has a variable disease course, novel prognostic markers and risk assessment models are being developed in order to identify high-risk patients who may need early treatment. The two tumor necrosis factor family proteins BAFF and APRIL and their receptors BAFF-R, TACI and BCMA are considered to play a critical role in the survival of normal B cells. In order to highlight the pathophysiological role of this complicated biological network, we aimed to analyze the potential prognostic effects of BAFF, APRIL, TACI and BCMA in CLL patients. We investigated the prognostic impact of serum BCMA, TACI, BAFF and APRIL levels in 129 newly diagnosed CLL patients [median age: 64 (39-88) years; male/female: 85/44]. Serum BAFF, TACI and BCMA levels were significantly lower in the patient group compared to the control group (p < 0.001), while serum APRIL level did not differ significantly between two groups (p > 0.05). Serum BCMA [(p = 0.029; r = 0.208)] and TACI levels [(p = 0.011; r = 0.241)] were positively correlated with serum free light chain ratio. Serum BAFF [(p = 0.008; r = - 0.236)] and BCMA [(p = 0.042; r = - 0.183)] levels were negatively correlated with Rai stage. Overall survival (OS) was relatively better in patients with low serum BAFF levels [60 (1-187) months vs 39.5 (0-256) months; p = 0.063]. Probability of OS was higher in patients with low BAFF levels when compared to patients with normal levels, without statistical significance (53.6% vs 23.6%; p > 0.05). Large prospective studies are needed to validate the prognostic role of this essential biological pathway in CLL.

Lymphocytes B Development After Kidney Transplantation

Introduction Alloantibodies are commonly used in kidney transplantation for donor/recipient immune matching as well as a marker of organ rejection after transplantation. In a broader context, anti-HLA antibodies development is associated with humoral response and B cells differentiation to long-lived memory cells. Recently studies on operational tolerance pointed to characteristic B cell phenotype and molecular signature. Thus, immune markers of anti-HLA antibodies development could point to early humoral immunity activation and may be beneficial for personalized risk stratification. Materials and Methods Low-risk kidney transplant recipients (n=53) were followed-up to 24 months after transplantation for alloantibodies development and organ rejection. Every three months anti-HLA antibodies, lymphocytes B phenotype, and cytokines were assessed. Memory B lymphocytes phenotype was recognized as CD27+ cells, both IgM positive and negative. In contrary naïve B cells were identified as CD27- and CD5+ B lymphocytes. Th1/Th2 and BAFF serum levels were measured with Luminex solid phase assay. Results and Discussion For the 34 recipients, alloantibodies were not present after transplantation, while for 19 others DSA antibodies were confirmed. The higher rate was observed 20 months after transplantation. Anti-HLA antibodies development was proceeded by increased in BAFF and INFgamma levels, as well as memory B lymphocytes numbers. It was found, that alloantibodies development was correlated with a number of memory B cells, Rs=0,96 (Spearman rank correlation). Conclusion Lymphocytes B phenotype monitoring after kidney transplantation is useful for alloantibodies development and may serve as an additional marker of humoral immunity activation. These could be also beneficial for individual risk stratification and tailored immunosuppression protocol development after kidney transplantation. National Centre for Research and Development, Poland (No. STRATEGMED1/233368/1/NCBR/2014). National Science Centre, Poland (No. NN402420738 and NN402 562440).

Significant elevation of the levels of B-cell activating factor (BAFF) in patients with sarcoidosis.

B-cell activating factor (BAFF) plays an important role in the survival and differentiation of B-cells and production of antibodies. Recent studies show that the serum BAFF levels are elevated in patients with sarcoidosis; however, they have not studied the relationship of the finding with the clinical features of the disease. The purpose of the present study is to analyze the BAFF and to elucidate the relationship between BAFF levels and the disease activity or severity of sarcoidosis. Eighty-eight patients with sarcoidosis and 21 healthy volunteers were enrolled in the present study. The BAFF levels were measured by an enzyme-linked immunosorbent assay. To assess the disease severity, we examined the number of affected organs, Schadding stages, respiratory function impairment (RFI), and the scoring system developed by Wasfi et al. The serum BAFF levels in sarcoidosis patients were significantly higher than those in healthy volunteers (median 1553.0 vs 984.6pg/ml, p < 0.001). There were positive correlations between the serum BAFF level and disease activity markers. In addition, there were positive correlations between the BAFF levels and the disease severity score in both the serum (R = 0.367, p < 0.001) and bronchoalveolar lavage fluid (BALF) (R = 0.376, p < 0.001). This study demonstrated that the BAFF levels in both the serum and BALF were positively correlated with the disease activity markers and disease severity. BAFF may be useful as an indicator of both the disease activity and severity.

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

ObjectivesTNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this...

IL10 restrains autoreactive B cells in transgenic mice expressing inactive RAG1

IL10 plays a dual role in supporting humoral immunity and inhibiting inflammatory conditions. B cells producing IL10 are thought to play a key regulatory role in maintaining self-tolerance and suppressing excessive inflammation during autoimmune and infectious diseases, primarily by inhibiting associated T cell responses. The extent to which B cells, through the provision of IL10, might function to sustain or inhibit autoantibody production is less clear. We previously described transgenic mice expressing catalytically inactive RAG1 (dnRAG1 mice), which show expansion of an IL10-compentent CD5+ B cell subset that phenotypically resembles B10 B cells, hypogammaglobulinemia, and a restricted B cell receptor repertoire with features indicative of impaired B cell receptor editing. We show here that B10-like B cells in dnRAG1 mice bind the membrane-associated autoantigen phosphatidylcholine (PtC), and that in vitro lipopolysaccharide (LPS) stimulation of dnRAG1 splenocytes induces a robust IgM response enriched in reactivity toward lupus-associated autoantigens. This outcome was correlated with detection of sIgMhi B cell populations that were distinct from, but in addition to, sIgMint populations observed after similar treatment of wild-type splenocytes. Loss of IL10 expression in dnRAG1 mice had no significant effect on B10-like B cell expansion or the frequency of PtC+ B cells. Compared to IL10+/+ dnRAG1 mice, levels of serum IgM, but not serum IgG, were highly elevated in some naïve IL10−/− dnRAG1 mice, and was correlated with a significant increase in serum BAFF levels. Differentiation of sIgMint B cells from LPS-stimulated dnRAG1 splenocytes was enhanced by loss of IL10 expression and IL10 blockade, but was suppressed by treatment with recombinant IL10. In vitro LPS-induced differentiation and antibody production was inhibited by treatment with JAK/STAT inhibitors or a synthetic corticosteroid, independent of IL10 expression and genotype. Taken together, these data suggest that IL10 expression in dnRAG1 mice maintains suppression of IgM levels in part by inhibiting BAFF production, and that regulatory B10-like B cells, through the provision of IL10, constrains B cell differentiation in response to mitogenic stimuli. Furthermore, autoantibody profiling raises a possible link between CD5+ B cell expansion, mitogenic stimulation, and autoantibodies associated with autoimmune complications observed in lupus and lupus-related disorders.

B-cell activating factor and related genetic variants in lupus related atherosclerosis

BackgroundSystemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with an increased atherosclerotic risk compared to healthy population, partially explained by traditional cardiovascular (CV) risk factors. Recent data suggest B-cell activating factor (BAFF) as an important contributor in the pathogenesis of both SLE and atherosclerosis. The aim of the current study is to explore whether serum BAFF levels along with variants of the BAFF gene increase lupus related atherosclerotic risk. Patients-Methods250 SLE patients underwent assessment of plaque formation and/or intimal media thickness (IMT) measurements in carotid and femoral arteries by ultrasound. Disease related features and CV traditional risk factors were also assessed. Serum BAFF levels were determined by commercially available ELISA and five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) were evaluated by PCR-based assays in all patients and 200 healthy controls (HC) of similar age and sex distribution. SLE patients were further divided in high and low BAFF groups on the basis of the upper quartile level of the distribution (1358 pg/ml). Genotype and haplotype frequencies in SLE patients and HC were determined by SNPStats and SHEsis software. ResultsHigh-BAFF SLE group displayed increased rates of both plaque formation and arterial wall thickening (defined as IMT>0.90 mm) compared to patients with low BAFF levels (58.1% vs 43.6%, p:0.048 and 38.6% vs 23.2%, p-value: 0.024, respectively). The association remained significant after disease related features were taken into account (ORs [95%CI]: 2.2 [1.0–5.1] and 2.5 [1.1–5.5] for plaque formation and arterial wall thickening, respectively). Moreover, the presence of the AA genotype of the rs12583006 BAFF gene variant increased susceptibility for both lupus and lupus related plaque formation (ORs [95%CI]: 2.8 [1.1–7.1], and 4.4 [1.3–15.4] in the codominant model, respectively). Finally, the haplotype TTTAT was found to be protective for plaque formation among SLE patients (OR 0.3 [0.1–0.9]. No associations between BAFF gene variants with arterial wall thickening were detected. ConclusionsHigh BAFF serum levels in the upper 4th quartile as well as BAFF genetic variants seem to increase susceptibility for both lupus and lupus related subclinical atherosclerosis implying B-cell hyperactivity as a potential contributor in the pronounced lupus related atherosclerotic risk.

Testosterone is an endogenous regulator of BAFF and splenic B cell number

Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.

B Cell Activating Factor (BAFF) in Long-term Kidney Transplant Recipients Is Not a Prognostic Marker for Allograft Dysfunction or Survival

ObjectiveB cell activating factor (BAFF) has been shown to play a role in B cell survival, maturation, and activation, and has been linked with renal transplant outcome. BAFF signaling has been associated with plasmablast survival, anti-HLA immunization, and loss of graft function. We aimed to analyze the interplay between BAFF, memory B cells, and plasmablasts in relation to allograft function in long-term kidney transplant (KTx) recipients and their anti-HLA sensitization. Materials and MethodsThis study included 70 long-term KTx recipients on standard immunosuppression 15 ± 6 years post transplantation (44 stable, 26 chronic allograft dysfunction, CAD) and 25 healthy volunteers. CD19+ B cells, memory B cells (CD19+CD27+), and plasmablasts (CD19+CD24-CD27++CD38++) were enumerated with flow cytometry. BAFF serum level and anti-HLA antibodies were assessed by Luminex bead arrays. ResultsWe found no difference in BAFF levels between KTx recipients and controls (median, interquartile range: 1.67, 1.40–1.97 vs 1.78, 1.63–1.93 ng/mL, P = .478) and no correlation between BAFF level and cell counts. Recipients presented lower plasmablast count than controls (22.5, 8–57 vs 79, 48–166 cells/mL, P < .001). There was a positive correlation between estimated glomerular filtration rate and plasmablasts (rs = 0.30, P = .013) in recipients. Cell populations and BAFF were not related to the presence of anti-HLA antibodies. None of the parameters investigated was related to deterioration of allograft function during the 2-year follow-up. ConclusionBAFF serum level is not related to anti-HLA sensitization, circulating memory B cells, plasmablast count, or allograft function. Circulating plasmablasts are associated with current allograft function but are not prognostic for future course.

Serum BAFF in Indian patients with IIM: a retrospective study reveals novel clinico-phenotypic associations in children and adults.

We studied the serum levels of B cell survival factors BAFF and APRIL in patients with idiopathic inflammatory myositis (IIM) and their relation with clinical and autoantibodies. Seventy-five patients (51 females and 24 males) with IIM (Bohan and Peter's criteria 1975) and 25 healthy adults were analyzed for BAFF, APRIL and IL-17 by ELISA, and myositis-specific and associated antibodies (MSA and MAA)using line immunoblot assay. Of the75 patients, 59 were adults, 42 had Dermatomyositis (DM), and 17 had Polymyositis. Median disease duration was 5 (3-12) months. BAFF levels were higher in IIM than healthy controls [p = 0.001], and in children with jDM than adults [p = 0.026]. BAFF levels were higher in adults with arthritis [p = 0.018], weight loss [p = 0.007], and PAH [p = 0.004]. Among the various MSAs, lowest levels were seen in those with anti-SRP [p = 0.043]. Median follow-up duration was 145 patient years. Twelve patients relapsed, while nine were in drug-free remission. BAFF were similar between these groups. Serum APRIL levels were elevated in limited number of patients with myositis, and the levels did not differ amongst the clinico-serologic phenotypes. IL-17 levels were higher in individuals positive for anti-SRP [p = 0.028]. Serum BAFF levels are elevated in IIM, more so in children. BAFF levels may be useful as biomarker for PAH and arthritis. Anti-SRP positivity is associated with elevated IL-17 levels suggesting rolein pathogenesis.

Peripheral B-Cell Subset Distribution in Primary Antiphospholipid Syndrome.

Background: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and to compare them with SLE patients and healthy controls (HC). Methods: Cross-sectional study including three study groups: 37 patients with pAPS, 11 SLE patients, and 21 age- and gender-matched HC. We determined the frequencies of different B-cell subsets in peripheral blood naïve and memory compartments. In addition, we measured serum B cell-activating factor (BAFF) levels and circulating pro-inflammatory cytokines, such as IL-6, by commercial ELISA and CBA, respectively. Results: Patients with pAPS showed a lower percentage of immature and naïve B cells than patients with SLE (p = 0.013 and p = 0.010, respectively) and a higher percentage of non-switched memory B cells than patients with SLE (p = 0.001). No differences either in the percentage of switched memory cells or plasma cells were found among the different groups. Serum BAFF levels were higher in SLE patients than in healthy controls and pAPS patients (p = 0.001 and p = 0.017, respectively). A significant increase in the serum BAFF levels was also observed in pAPS patients compared to HC (p = 0.047). Circulating IL-6 levels were higher in SLE and pAPS patients than HC (p = 0.036 and p = 0.048, respectively). A positive correlation was found between serum BAFF and IL-6 levels in patients with SLE but not in pAPS (p = 0.011). Conclusions: Our characterization of peripheral blood B-cell phenotypes in pAPS demonstrates different frequencies of circulating B cells at different stages of differentiation. These differences in the naïve B-cell repertoire could explain the higher number and variety of autoantibodies in SLE patients in comparison to pAPS patients, especially in those with obstetric complications.

B-cell activating factor, a predictor of antibody mediated rejection in kidney transplantation recipients.

Donor-specific antibody (DSA) is a widely-used biomarker for antibody-mediated rejection (ABMR) but correctly indicates only 30-40% of patients with ABMR. Additional biomarkers of ABMR in kidney transplant recipients are needed. All 68 kidney transplanted-recipients enrolled in this study were negative for graft rejection as determined by surveillance-biopsy ELISA at day 7 post-transplantation. Allograft biopsy was then performed at 6months post-transplantation for subclinical-ABMR detection. Recipients were stratified by pre-transplant DSA and BAFF at day 7 into four groups. During the study period, 13.2% of the recipients demonstrated subclinical-ABMR at 6months, without patient with clinical ABMR presentations. Overall mean BAFF at day 7 was 393pg/mL (95% CI=316-471pg/mL). The optimal cut-off value for low vs. high BAFF level was 573pg/mL, with sensitivity and specificity at 77.8% and 88.1%, respectively. Fifty percent of recipients with high BAFF at day 7 (14 patients) and only 3.7% of patients with low BAFF demonstrated ABMR (P<0.05). Indeed, ABMR was more common in patients high BAFF level (hazard ratio=7.30; 95% CI=3.77-14.15). The prevalence of ABMR among negative pre-transplant DSA/low BAFF, positive DSA/low BAFF, negative DSA/high BAFF, and positive DSA/ high BAFF recipients were 4.4, 0, 37.5 and 66.7%, respectively (P<0.05). Post-transplant ABMR can be predicted by perioperative serum BAFF level. Together with DSA testing, BAFF provides additional predictive value for ABMR.