Role Of BAFF Research Articles

Association between levels of serum and urinary B cell-activating factor and systemic lupus erythematosus disease activity.

This study investigated the correlation between serum and urinary B cell-activating factor (BAFF) levels and systemic lupus erythematosus (SLE) disease activity. This case-control study was conducted with 87 participants between December 2020 and September 2021. Sixty-two SLE patients who fulfilled the eligibility criteria were enrolled. SLE patients were categorized into active (n=34) and inactive (n=28) groups based on their Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores. The control group consisted of 25 healthy subjects. Serum and urine samples were collected for the measurement of BAFF levels. Finally, the relationship between these variables and SLE disease activity was investigated. The mean age of active (SLEDAI-2K >4) and inactive (SLEDAI-2K ≤4) SLE patients and healthy individuals were 32.8±7.8, 32.5±6.8, and 31.7±7.8 years, respectively (p=0.62). The median serum BAFF (s-BAFF) and urinary BAFF (u-BAFF) in active lupus patients (10.4 [2.3] ng/mL and 8.2 [3.7] ng/mL, respectively) were significantly higher than in inactive lupus patients (6 (7.1) ng/mL and 1.7 (4.7) ng/mL, respectively; p<0.001) and the control group (3 (3.7) ng/mL and 1.6 (2.2) ng/mL, respectively; p<0.001). However, s-BAFF (p=0.07) and u-BAFF (p=0.43) did not significantly differ between the inactive group and the control group. A significant positive correlation was observed between s-BAFF (r=0.41 and p=0.001) and u-BAFF (r=0.78 and p<0.001) levels and the SLEDAI-2K score. There is a significant positive correlation between serum and urinary BAFF levels and SLE disease activity. Furthermore, significantly higher levels of s-BAFF and u-BAFF have been observed in patients with active lupus compared to inactive and healthy subjects, indicating a possible role for BAFF in the pathogenesis of SLE disease activity.

Abstract 443: BAFF Neutralization Impairs The Regression Of Insulin Resistance In Diabetic Mice By Modulating The Innate Immune Response

Adults with type 2 diabetes have a two-to-three-fold increased risk of cardiovascular diseases. B cell activating factor (BAFF), a tumor necrosis factor superfamily member, is implicated both in diabetes and cardiovascular diseases, and hence a therapeutic target of interest. High levels of BAFF are known to promote autoantibody synthesis and autoimmune diseases. We examined if BAFF neutralization with an anti-BAFF antibody improves glucose intolerance in a model of regression of insulin resistance in diabetic mice. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks and segregated into two groups based on their glucose intolerance determined by a glucose tolerance test. Each group was simultaneously switched from HFD to a normal chow diet and received injections of anti-BAFF or an isotype control antibody every 2 nd week for a total of 6 weeks. As expected, body weights decreased in both groups parallel with the increase in insulin sensitivity. Unexpectedly, the BAFF-neutralized mice had impaired regression of insulin resistance compared to the control mice. Extensive cellular phenotyping of immune cells indicated systemic depletion of only the B2 cells and lower levels of circulating autoantibodies in the BAFF-neutralized mice. Gonadal white adipose tissue (gWAT) was the primary source of BAFF, and no differences in the M1 and M2 macrophages, eosinophils, natural killer cells, helper T cells, and cytotoxic T cell populations were found. RNA sequencing analysis of stromal vascular fraction from gWAT revealed impaired B cell receptor signaling, immunoglobulin production, complement activation, and phagocytosis pathways in the BAFF-neutralized mice. In this line, (i) an increased number of dead adipocytes, (ii) decreased levels of IgG2b and IgM, (iii) increased citrullinated histone H3, neutrophils, and DNA extracellular traps were found in the gWAT of BAFF-neutralized mice. These results suggest attenuated humoral response and a dominant and harmful role of innate response in the gWAT following BAFF neutralization in late-stage obesity. Since anti-BAFF biologics are approved for the treatment of lupus patients, our results highlight the need for further studies on the role of BAFF in late-stage obesity and diabetes.

BAFF induces CXCR5 expression during B cell differentiation in bone marrow

B cell activating factor (BAFF) plays an important role in antibody production through differentiation and maturation of B cells mainly in secondary lymphoid organs. On the other hand, the role of BAFF in the bone marrow, the primary lymphoid organ of B cell development, has not been well elucidated. Here, effects of BAFF in bone marrow B cell development were examined by using BAFF-deficient mice. When mRNA expression levels of B cell differentiation markers including Cd19, Bcl2, Igμ, Il7r and Cxcr5 were compared between bone marrow of wild-type and BAFF-KO mice, a lower level of Cxcr5 expression was found in the KO mice. Additionally, protein expression of CXCR5 on IgM+ cells in the bone marrow was decreased by BAFF deficiency. In vitro studies also confirmed the effect of BAFF on CXCR5 by IgM+ cells; culturing bone marrow cells from BAFF-KO mice with BAFF in vitro increased the proportion of CXCR5+ cells in IgM+ cells compared with non-treated bone marrow cells. In addition, BAFF synergized with TNF-α and IL-6 to increase the expression of CXCR5+ on IgM+ cells. The BAFF-mediated up-regulation of CXCR5 expression was reproduced by using CD19+ cells purified from BAFF-KO bone marrow cells, suggesting that BAFF directly affects B-lineage cells in bone marrow to promote CXCR5 expression. Together, this study suggests that BAFF has an important role in B cell differentiation in bone marrow by directly inducing CXCR5 expression which affect their migration to secondary lymphoid organs.

Belimumab or anifrolumab for systemic lupus erythematosus? A risk-benefit assessment.

Treatment of systemic lupus erythematosus (SLE) currently employs agents with relatively unselective immunosuppressive properties. However, two target-specific biological drugs have been approved: belimumab (anti-B-cell-activating factor/BAFF) and anifrolumab (anti-interferon alpha receptor-1/IFNAR1). Here, we performed a comparative risk-benefit assessment for both drugs based on the role of BAFF and IFNAR1 in host defense and the pathogenesis of SLE and by considering the available data on safety and efficacy. Due to differences in target expression sites, anti-IFNAR1, but not anti-BAFF, might elicit organ-specific effects, consistent with clinical efficacy data. The IFNAR1 is specifically involved in innate and adaptive antiviral immunity in most cells of the body. Consistent with this observation, the available safety data obtained from patients negatively selected for LN and neuropsychiatric SLE, primary immunodeficiencies, splenectomy and chronic HIV, HBV, HCV infections suggest an increased risk for some viral infections such as varicella zoster and perhaps influenza. In contrast, BAFF is mainly involved in adaptive immune responses in lymphoid tissues, thus anti-BAFF therapy modulates SLE activity and prevents SLE flares without interfering with local innate host defense mechanisms and should only marginally affect immune memory to previous pathogen exposures consistent with the available safety data from SLE patients without chronic HIV, HBV or HCV infections. When using belimumab and anifrolumab, careful patient stratification and specific precautions may minimize risks and maximize beneficial treatment effects for patients with SLE.

B cell activating factor regulates periodontitis development by suppressing inflammatory responses in macrophages

BackgroundB cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily with immunomodulatory effects on both innate and adaptive immune responses. Periodontitis is an inflammatory disease characterized by periodontal soft tissue inflammation and the progressive loss of periodontal ligament and alveolar bone. Macrophages are closely related to periodontitis progression. However, the role of BAFF in periodontitis development and macrophage polarization and the underlying mechanism remain unknown.MethodsIn vivo, a ligation-induced mouse model of periodontitis for BAFF blockade was established to investigate the expression of inducible nitric oxide synthase (iNOS) through real-time PCR (RT-PCR) and immunohistochemistry. In addition, the level of TNF-α in the periodontium, the number of osteoclasts, and alveolar bone resorption were observed. In vitro, RAW 264.7 macrophage cells were treated with 100 ng/mL Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in either the presence or absence of 50 nM small interfering RNA (siRNA) targeting BAFF, followed by further incubation for 24 h. These cells and supernatants were collected and stored for RT-PCR, enzyme-linked immunosorbent assay, western blotting and immunofluorescence microscopy.ResultsIn vivo, BAFF blockade decreased the levels of TNF-α in the periodontium in a ligature-induced mouse periodontitis model. Reduced osteoclast formation and lower alveolar bone loss were also observed. In addition, BAFF blockade was related to the expression of polarization signature molecules in macrophages. In vitro, BAFF knockdown notably suppressed the production of TNF-α in RAW 264.7 cells stimulated by P. gingivalis LPS. Moreover, BAFF knockdown attenuated the polarization of RAW 264.7 cells into classically activated macrophages (M1), with reduced expression of iNOS.ConclusionsBased on our limited evidence, we showed BAFF blockade exhibits potent anti-inflammatory properties in mice experimental periodontitis in vivo and in P. gingivalis LPS-treated RAW 264.7 cells in vitro, and macrophage polarization may be responsible for this effect.

The role of BAFF and G-CSF for rituximab-induced late-onset neutropenia (LON) in lymphomas

Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case–control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20+ B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.

Rapamycin Modulates the Proinflammatory Memory-Like Response of Microglia Induced by BAFF.

BackgroundRecently trained immunity of microglia provided an opportunity to study the chronic effect of microglial activation and its metabolic rewiring in neuroimmunological diseases. Since elevated levels of B cell-activating factor (BAFF) have been proved to be associated with some chronic neuroimmunological disorders. Here, we used the trained innate immunity model to analyze the effect of BAFF, a vital regulator of the adaptive immune system, on long-term microglial activation and metabolic reprogramming in vitro and in vivo.Methods and resultsIn vitro, BV2 cells and mouse primary microglial cells were incubated with BAFF for 24 h (BAFF priming). After 5 days of resting, microglia were restimulated with LPS (LPS restimulation) or BAFF (BAFF restimulation). BAFF priming induced a pro-inflammatory trained immunity-phenotype of both BV2 cells and primary microglial cells, which was indicated by morphological change, secretion of pro-inflammatory cytokine and chemokine upon LPS restimulation or BAFF restimulation. The production of lactate and NAD+/NADH ratio were elevated 5 days after BAFF priming. The activation of the Akt/mTOR/HIF-1α pathway was induced by BAFF priming and lasted for 5 days. Pretreating the BV2 cells or mouse primary microglial cells with rapamycin blocked mTOR/HIF-1α activation and cellular metabolic reprogramming induced by BAFF training. Consistently, rapamycin efficiently suppressed the trained immunity-like responses of microglia triggered by BAFF. In vivo, adult male mice were treated with BAFF by intracerebroventricular injection for priming and 7 days later with BAFF for restimulation. BAFF training activated microglia in the cortex and hippocampus. The production of proinflammatory cytokines and chemokines was elevated after BAFF training.ConclusionOur current data, for the first time, demonstrate that BAFF priming induces a proinflammatory memory-like response of microglia not only to LPS but also to BAFF itself. Rapamycin inhibits microglial priming triggered by BAFF through targeting the mTOR/HIF-1α signaling pathway. Our data reveal a novel role of BAFF in trained immunity and that rapamycin may be a potential therapeutic target of neuroimmunological diseases.

Circulating BAFF and CXCL10 levels predict response to pegylated interferon in patients with HBeAg-positive chronic hepatitis B.

B-cell activating factor (BAFF), an essential cytokine for B lymphocytes activation, has been implicated in the pathogenesis of chronic viral hepatitis. However, the role of BAFF in patients with chronic hepatitis B (CHB) undergoing antiviral therapy is unknown. Patients with HBeAg-positive CHB treated with 48-week pegylated interferon (PEG-IFN; n = 42), who had stored plasma samples during treatment were recruited. Serial plasma levels of BAFF and C-X-C motif chemokine 10 (CXCL10) during therapy were measured. Combined response (CR), defined as HBeAg seroconversion with HBV DNA < 2,000 IU/mL plus HBsAg decline ≥ 1 log10 IU/mL at 24 weeks post-treatment, was achieved in 11 (26.2%) patients. BAFF levels were elevated during treatment but decreased to pre-treatment levels after PEG-IFN cessation in both responders and non-responders. Low baseline BAFF (< 770 pg/ml) and high CXCL10 (≥ 320 pg/ml) levels were independently associated with CR in multivariate analysis. Baseline CXCL10/BAFF ratio of ≥ 0.45 was predictive of CR with positive and negative predictive values of 61.5 and 89.7%, respectively. In summary, low baseline BAFF and high CXCL10 levels were associated with treatment response to PEGIFN. The combined measurement of these immune markers may help individualized decision-making in patients with HBeAg-positive CHB.

B-cell activating factor (BAFF) expression is associated with Crohn's disease and can serve as a potential prognostic indicator of disease response to Infliximab treatment

BackgroundSeveral studies correlated elevated B-cell activating factor (BAFF) levels and its polymorphisms (SNPs) in patients with autoimmunity. Limited data existed regarding the role of BAFF in Crohn's Disease (CD) susceptibility and/or treatment response to infliximab. AimThis study aims to evaluate BAFF expression in CD patients, investigate if its expression can predict response to infliximab treatment, and examine the association of BAFF SNPs with CD susceptibility. MethodsOne hundred twelve CD patients and 164 healthy controls were recruited. Serum BAFF levels were determined using an enzyme-linked immunosorbent assay. Participants were genotyped for rs9514828, rs1041569 and rs2893321 SNPs. ResultsSerum BAFF concentration was elevated in CD patients (472.86 ± 223.60 pg/ml) compared with controls (128.16 ± 70.10 pg/ml) before treatment. Responders to IFX treatment had increased serum BAFF levels at baseline (610.03 ± 167.55 pg/ml) compared to non-responders (267.09 ± 107 pg/ml). In responders, BAFF concentration reduced after IFX administration, while increased in non-responders. The rs1041569, TA and AA genotypes frequencies, and the minor allele A were increased significantly in CD patients, indicating an association of the SNP with CD susceptibility. ConclusionsOur study suggests that BAFF could be a potential biomarker of CD, while SNP rs1041569 was associated with CD susceptibility.

BAFF-driven NLRP3 inflammasome activation in B cells

BAFF supports B-cell survival and homeostasis by activating the NF-κB pathway. While NF-κB is also involved in the priming signal of NLRP3 inflammasome, the role of BAFF in NLRP3 inflammasome regulation is unknown. Here we report BAFF engagement to BAFF receptor elicited both priming and activating signals for NLRP3 inflammasomes in primary B cells and B lymphoma cell lines. This induction of NLRP3 inflammasomes by BAFF led to increased NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, and pyroptosis. Mechanistically, BAFF activated NLRP3 inflammasomes by promoting the association of cIAP-TRAF2 with components of NLRP3 inflammasomes, and by inducing Src activity-dependent ROS production and potassium ion efflux. B-cell receptor (BCR) stimulation on the Lyn signaling pathway inhibited BAFF-induced Src activities and attenuated BAFF-induced NLRP3 inflammasome activation. These findings reveal an additional function of BAFF in B-cell homeostasis that is associated with BCR activities.

B-Cell Activating Factor Secreted by Neutrophils Is a Critical Player in Lung Inflammation to Cigarette Smoke Exposure.

Cigarette smoke (CS) is the major cause of chronic lung injuries, such as chronic obstructive pulmonary disease (COPD). In patients with severe COPD, tertiary lymphoid follicles containing B lymphocytes and B cell-activating factor (BAFF) overexpression are associated with disease severity. In addition, BAFF promotes adaptive immunity in smokers and mice chronically exposed to CS. However, the role of BAFF in the early phase of innate immunity has never been investigated. We acutely exposed C57BL/6J mice to CS and show early BAFF expression in the bronchoalveolar space and lung tissue that correlates to airway neutrophil and macrophage influx. Immunostaining analysis revealed that neutrophils are the major source of BAFF. We confirmed in vitro that neutrophils secrete BAFF in response to cigarette smoke extract (CSE) stimulation. Antibody-mediated neutrophil depletion significantly dampens lung inflammation to CS exposure but only partially decreases BAFF expression in lung tissue and bronchoalveolar space suggesting additional sources of BAFF. Importantly, BAFF deficient mice displayed decreased airway neutrophil recruiting chemokines and neutrophil influx while the addition of exogenous BAFF significantly enhanced this CS-induced neutrophilic inflammation. This demonstrates that BAFF is a key proinflammatory cytokine and that innate immune cells in particular neutrophils, are an unconsidered source of BAFF in early stages of CS-induced innate immunity.

The effects of BAFF on T lymphocytes in chronic obstructive pulmonary disease

BackgroundIt has been reported that B cell activating factor belonging to the tumor necrosis factor family (BAFF) expression is increased in chronic obstructive pulmonary disease (COPD). However its role in this chronic inflammatory disease is not fully understood. Previous studies have suggested that BAFF also affects T cell function. We therefore investigated the effects of BAFF on T lymphocytes in COPD.MethodsBAFF was detected in the cells of sputum and the plasma. Peripheral blood mononuclear cells (PBMCs) were isolated from COPD patients and treated with BAFF or BAFF plus BR3-Fc (BAFF antagonist). The apoptosis of CD4+ cells and CD8+ cells was analyzed by flow cytometry. CD4+ cells and CD8+ cells were isolated from peripheral blood of COPD patients respectively and treated with BAFF or BAFF plus BR3-Fc. Interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected in the CD4+ cells, and perforin and granzyme B were detected in the CD8+ cells.ResultsBAFF expression was increased in the cells of sputum and the plasma from COPD patients compared with control subjects. The plasma BAFF levels were inversely correlated with FEV1 percentage of predicted in patients with COPD. BAFF did not significantly alter the apoptosis of CD4+ cells, however it significantly inhibited the apoptosis of CD8+ cells from COPD patients. BAFF increased IFN-γ expression in the CD4+ cells from COPD patients, while it did not significantly alter the expresson of IL-4 in these cells. BAFF increased the expression of perforin and granzyme B in the CD8+ cells from COPD patients.ConclusionsOur findings indicate that BAFF may be involved in the inflammatory response in COPD via affecting T lymphocytes, suggesting a possible role of BAFF in the pathogenesis of COPD.

Association of BAFF gene polymorphisms with multiple sclerosis progression

The cytokine of the tumor necrosis factor (TNF) family B-cell activating factor (BAFF) (TNFSF13B) that regulates the proliferation, differentiation, and survival of B cells is assumed to be involved in the pathogenesis of multiple sclerosis (MS). Objective: to analyze the association of BAFF gene polymorphisms (rs1224141, rs9514827) with the progression rate and frequency of MS exacerbations. Patients and methods. A total of 100 Caucasian patients (24 males and 76 females) with relapsing-remitting MS, who were born and lived in the Altai Territory of the Russian Federation, were examined. Genotyping was performed by real-time polymerase chain reaction using competitive TaqMan probes. Results and discussion . The annual risk of a>0.75 point disability increase in the Expanded Disability Status Scale (EDSS) score was ascertained to be associated with the first remission duration of less than 2 years, with the G/G genotype of BAFF (rs1224141) in males and females, and with the C/C genotype of BAFF (rs9514827) in females. The likelihood of the first remission duration of less than 2 years was increased in female carriers of the G allele of BAFF (rs1224141). There was no association of BAFF gene polymorphisms (rs1224141, rs9514827) with the frequency of MS exacerbations. It seems promising to further study the role of BAFF in the pathogenesis of MS and the effect of this cytokine on the specific features of the course of the disease. The investigation results will be able to predict the efficiency of MS therapy with anti-BAFF drugs and to identify criteria for their individualized use. Conclusion. In patients with MS in the Altai Territory of the Russian Federation, the risk for a high MS progression rate is related to the carriage of BAFF genotypes with rare alleles in homozygous state: G/G polymorphism rs1224141, C/C polymorphism rs9514827 in combination with the female sex. The G allele of BAFF (rs1224141) in women is associated with the risk of the unfavorable prognostic duration of the first MS remission of less than 24 months.

Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF.

To determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an SLE-prone host. Starting with C57BL/6 mice that express a human BCL2 transgene (Tg) in their B cells (thereby rendering B cell survival largely independent of BAFF-triggered signals), we introgressed this Tg into NZM 2328 mice genetically deficient in BAFF (NZM.Baff-/- ) to generate NZM.Baff-/- .Bcl2Tg mice. Expression of human Bcl-2 and lymphocyte profiles were assessed by fluorescence-activated cell sorting, and serologic profiles were determined by enzyme-linked immunosorbent assay. Immunofluorescence and histologic analyses were performed to assess renal immunopathologic features in the mice, and clinical disease was assessed according to the outcomes of severe proteinuria and death. In comparison to their non-Tg NZM.Baff-/- littermates (n ≥ 7), NZM.Baff-/- .Bcl2Tg mice (n ≥ 8) overexpressed Bcl-2 in their B cells and developed significantly increased percentages and numbers of B cells and plasma cells, serum levels of IgG autoantibodies, glomerular deposition of IgG and C3, and severity of glomerular and tubulointerstitial inflammation, culminating in severe proteinuria and death (all P < 0.05 versus NZM.Baff-/- littermates). The time course for development of SLE-like features in NZM.Baff-/- .Bcl2Tg mice was more rapid than has been previously observed in NZM 2328 wild-type mice (median age at death 4.5 months versus 7.5 months). NZM.Baff-/- .Bcl2Tg mice remained responsive to BAFF, since reintroduction of the Baff gene into these mice further accelerated the course of disease (median age at death 3 months). The role of BAFF in the development of SLE-like disease may be dispensable as long as B cell survival is preserved via a BAFF-independent pathway. This may help explain the limited and variable clinical success with BAFF antagonists in human SLE. Thus, NZM.Baff-/- .Bcl2Tg mice may serve as a powerful murine model for the study of BAFF-independent SLE.

The role of BAFF and APRIL in rheumatoid arthritis.

Development and activation of B cells quickly became clear after identifying new ligands and receptors in the tumor necrosis factor superfamily. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are the members of membrane proteins Type 2 family released by proteolytic cleavage of furin to form active, soluble homotrimers. Except for B cells, ligands are expressed by all such immune cells like T cells, dendritic cells, monocytes, and macrophages. BAFF and APRIL have two common receptors, namely TNFR homolog transmembrane activator and Ca2+ modulator and CAML interactor (TACI) and B cell-maturation antigen. BAFF alone can also be coupled with a third receptor called BAFFR (also called BR3 or BLyS Receptor). These receptors are often expressed by immune cells in the B-cell lineage. The binding of BAFF or APRIL to their receptors supports B cells differentiation and proliferation, immunoglobulin production and the upregulation of B cell-effector molecules expression. It is possible that the overexpression of BAFF and APRIL contributes to the pathogenesis of autoimmune diseases. In BAFF transgenic mice, there is a pseudo-autoimmune manifestation, which is associated with an increase in B-lymphocytes, hyperglobulinemia, anti-single stranded DNA, and anti-double-stranded DNA antibodies, and immune complexes in their peripheral blood. Furthermore, overexpressing BAFF augments the number of peripheral B220+ B cells with a normal proliferation rate, high levels of Bcl2, and prolonged survival and hyperactivity. Therefore, in this review article, we studied BAFF and APRIL as important mediators in B-cell and discussed their role in rheumatoid arthritis.

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.

Profile of BAFF and its receptors’ expression in lupus nephritis is associated with pathological classes

Background/Objective B-cell activating factor (BAFF) plays an important role in the pathogenesis of systemic lupus erythematosus. However, the role of BAFF in lupus nephritis (LN) is not understood. Our aim was to evaluate the expression of BAFF and its three receptors in renal biopsy samples from patients with LN and investigate a relationship with pathological class. Methods We conducted a prospective descriptive study (2011-2014) on 52 kidney biopsy samples from patients with LN. Immunohistochemistry for BAFF, its receptors (transmembrane activator and calcium modulator and cyclophilin ligand interaction (TACI), protein maturation of B cells (BCMA), and BAFF-receptor (BAFF-R)), and CD20 expression was performed. Samples were scored according to the percentage of cells with positive expression. Results In class II LN, BAFF-R and TACI were not expressed, whereas BCMA and BAFF were lowly expressed in the interstitial inflammatory infiltrates. Proliferative class III/IV had elevated BAFF expression in the glomeruli, and TACI was expressed in interstitial inflammatory infiltrates and the glomeruli. Interestingly, the class IV cases with vasculopathy ( n = 4) had endothelial BAFF expression, which was not visible in thrombotic microangiopathy ( n = 4). Class V was characterized by low BAFF expression in interstitial inflammatory infiltrates and by BAFF, TACI, and BCMA expression in the glomeruli. BAFF expression was associated with inflammatory scores and CD20 positive infiltrates, mainly in class IV. Conclusions Expression patterns of BAFF and its receptors differ according to LN class. Our study provides evidence that BAFF could be used as a routine marker in LN biopsies and to determine which patients will benefit from anti-BAFF therapy.

Novel role for BAFF in tertiary lymphoid neogenesis

Novel role for BAFF in tertiary lymphoid neogenesis

B-cell activating factor regulates IL-1β- and IL-17A-mediated pulmonary fibrosis in mice

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. Methods The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin, an intercalating agent which causes DNA strand breaks. Lung fibrosis was evaluated in Baff deficient mice and in wild-type mice after neutralization of BAFF with BAFF-R-Ig. Lung cells from bleomycin-treated mice were collected at day 7, labeled with anti-CD115, anti-CD3, anti-CD19 and anti-Gr1 antibodies and sorted by FACS for evaluation of BAFF mRNA expression by qPCR. BAFF was quantified in bronchoalveolar lavage fluid (BALF) of controls and patients with IPF. Results We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1 + neutrophils as an important source of BAFF upon BLM induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β- and IL-17A-dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3 + T cells from murine fibrotic lungs ex vivo . Finally, we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Conclusion The present data, demonstrating a critical role of BAFF by amplifying the IL-17A effect in experimental lung fibrosis, together with increased BAFF levels in the airways of patients with IPF, suggest that BAFF might be a therapeutic target of IPF.

Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.

The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections. Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.