Levels of BAFF in serum in primary biliary cirrhosis and autoimmune diabetes

Levels of the B-cell activating cytokine BAFF are increased in serum in various autoimmune disease, and particularly Sj?gren's syndrome in which there is evident B-lymphocyte proliferation. Studies in two autoimmune disease in which B-cell proliferation is less evident, primary biliary cirrhosis (PBC), and adult-onset Type 1 diabetes, showed serum levels of BAFF to be mostly in the normal range. A single raised level among eight sera tested in one patient studied with autoimmune hepatitis (AH) coincided with a relapse of the disease. Increased levels of BAFF in human sera, indexing a potent antigenic drive on B-cell production and survival in some autoimmune diseases, may mark only particular stages in the evolution of such diseases.     

BAFF is elevated in serum of patients with Wegener's granulomatosis

BAFF (B-cell activating factor of the TNF family) plays a crucial role in B-cell survival. Elevated BAFF serum levels have been linked to several autoimmune diseases in humans, and therapies targeting BAFF were successful in animal models of rheumatoid arthritis and systemic lupus erythematosus. Wagener's granulomatosis (WG), a chronic systemic vasculitis, is characterized by circulating autoantibodies (cANCA) targeting neutrophils, which can produce BAFF. To investigate whether BAFF is involved in WG pathology, BAFF serum levels were measured by ELISA in 46 WG patients and 62 healthy donors. We report the novel finding that in WG patients serum levels of BAFF were significantly increased (median 3.95 ng/ml, p=0.009) compared to healthy controls (median 2.38 ng/ml). The difference was even more pronounced when comparing controls with untreated WG patients (median 4.61 ng/ml, p=0.001). Treatment of WG patients with glucocorticoids was associated with lower BAFF levels. The serum BAFF level in treated WG patients was about the same as in the control group. We propose that BAFF might be a pathogenic factor in WG and that targeting BAFF may represent a new therapeutic strategy in a subset of chronically relapsing WG patients with elevated BAFF levels.     

Abnormal expression of BAFF and its receptors in peripheral blood and skin lesions from systemic lupus erythematosus patients

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by abnormal T and B cells. B-cell activating factor (BAFF) has been suggested to play a crucial role in lupus by promoting the proliferation, differentiation, and survival of B cells. Increased serum levels of BAFF have been found in patients with lupus. However, the expression of BAFF and its receptors on immune cells and in skin has not been systematically reported before. Here, we report that SLE patients showed increased levels of BAFF on circulating CD3⁺ T cells and B-cell maturation antigen (BCMA) on CD14⁺ monocytes and dramatically increased expression of BAFF in lupus skin lesions compared with those of healthy controls. TACI was undetectable on circulating immune cells. An increased serum level of BAFF was also confirmed in lupus patients in this study. Our findings may provide a better understanding of the pathogenesis and predictors of BAFF antibody treatment response, as well as potential targets for skin therapies.     

增殖诱导配体在自身免疫病患者外周血中的表达

为检测增殖诱导配体(APRIL)在自身免疫病(SLE和RA)患者中的表达情况以及它与B细胞刺激因子(BAFF)表达、疾病预后、抗-dsDNA抗体之间的相关性。收集58名自身免疫病患者以及20名健康对照的外周血,用实时定量RT-PCR方法检测PBMC中APRIL和BAFF mRNA的表达,用ELISA方法检测血浆中APRIL和BAFF蛋白水平。同时,检测血浆中IgG、IgA、IgM、BF和抗-dsDNA抗体水平。结果同对照组相比,APRIL mRNA水平在自身免疫病患者中显著升高,与BAFF mRNA表达水平有相关性。与疾病初发组和治疗后缓解组相比,治疗后来缓解组患者APRIL mRNA表达显著升高。疾病组外周循环中BAFF蛋白显著升高,APRIL蛋白未见升高,APRIL和BAFF之间未见显著意义相关性,A-PRIL蛋白与抗-dsDNA和疾病活动度之间未见显著相关。检测APRIL mRNA含量是判断自身免疫病患者治疗情况和疾病预后的有用指标。循环中APRIL和BAFF蛋白的产生可能受到不同机制调节,在自身免疫病的发生、发展以及转归中所起的作用也不同,为研究APRIL的产生机制、表达水平和自身免疫病程度、早期诊断、预后等的关系打下基础。     

Elevated serum B-cell activating factor in patients with chronic urticaria

The B and T cells abnormalities that have been described among CU patients, lend support to its regard as an autoimmune disease. In this study we compared serum B-cell activation factor (BAFF) levels in 46 CU patients to 24 healthy controls and evaluated a possible association between elevated serum BAFF in CU patients and the presence of autologous serum skin test, anti-thyroid antibodies, antinuclear antibodies, high total IGE levels, and urticaria disease severity. We found that serum BAFF levels is elevated statistically significant in CU patients compared to healthy control (1228±342 pg/ml vs. 758±313 pg/ml, P<0.0001). CU patients with severe disease activity had significantly higher serum BAFF levels compared to patients with mild CU (1394.6±299.6 vs. 1097.6±221.3, P=0.0008). No association was found between the presence of positive autologous serum skin test, anti-thyroid antibodies or antinuclear antibodies or high levels of total IgE and serum BAFF levels in CU Patients. We conclude that CU patients have higher levels of serum BAFF which associate with disease severity.     

Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review

B-cell-activating factor (BAFF) influences peripheral B-cell survival, maturation and immunoglobulin class-switch recombination and has a range of potential clinical implications. Biological functions of BAFF and its relevance in various clinical disorders including currently investigated BAFF-targeting therapies are reviewed and discussed based on PubMed search of relevant articles. Serum levels of BAFF are increased in autoimmune diseases including autoimmune hepatitis and primary biliary cirrhosis where BAFF concentrations are related to titres of autoantibodies and disease progression. Increased BAFF levels are found in synovial, bronchoalveolar and gut lavage fluids, suggesting local class switching and immunoglobulin production. Clinical relevance and diagnostic potential of BAFF are also noted in patients with allergic diseases, malignancies and infections including hepatitis C virus. BAFF antagonists are promising new therapeutic agents, currently being tried in B-cell-related autoimmune diseases. Serum level of BAFF may indicate disease mechanisms and the degree of activity. Determination of BAFF in different body compartments like synovium, airways and gut may also have clinical implications. Results of ongoing clinical trials with BAFF antagonists are eagerly awaited.     

Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases

The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials. These include the BAFF/APRIL dual inhibitor, atacicept, and the BAFF inhibitor, belimumab, which is approved as an add-on therapy for patients with active SLE. Post hoc analyses of these trials indicate that baseline serum levels of BAFF and BAFF/APRIL correlate with treatment response to belimumab and atacicept, respectively, suggesting a role for the two molecules as predictive biomarkers. It will, however, be important to refine future testing to identify active forms of BAFF and APRIL in the circulation, as well as to distinguish between homotrimer and heteromer configurations.

In this review, we discuss the rationale for dual BAFF/APRIL inhibition versus single BAFF inhibition in autoimmune disease, by focusing on the similarities and differences between the physiological and pathogenic roles of the two molecules. A summary of the preclinical and clinical data currently available is also presented.     

BAFF: a local and systemic target in autoimmune diseases

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF‐R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation‐inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)‐6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.     

B-cell activating factor levels in rheumatoid arthritis patients in response to treatment with biologics

The B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, has recently attracted attention as a potent cytokine, involved in B-cell stimulation and survival of autoimmune cells. Despite its significance in the pathogenesis of autoimmune diseases, data is limited and inconclusive regarding its expression in different stages of rheumatoid arthritis (RA). The aim of this study was to assess BAFF in biologic-na?ve RA patients with early versus established disease and monitor its levels in response to anti-TNF treatment in seronegative- and seropositive patients. Based on our results, B-cell-activating factor (BAFF) did not appear to be overexpressed or differentially expressed early (≤2 years duration) in comparison to established rheumatoid arthritis (RA). Moreover, tumor necrosis factor (TNF) blockade did not appear to affect BAFF levels in either seropositive or seronegative RA patients, despite the association of anti-TNF treatment with the development of autoantibodies and the known anti-apoptotic effects of BAFF. As expected, BAFF became induced after B-cell depletion. Investigation of the effect of different biologics on the expression of BAFF and other cytokines will help elucidate the interconnecting immune pathways involved in the initiation and perpetuation of the inflammatory process.     

Elevated serum BAFF levels in patients with autoimmune hepatitis

Serum cytokines are thought to be involved in autoimmune hepatitis (AIH) pathogenesis via immune dysregulation. B-cell activating factor belonging to the tumor necrosis factor family (BAFF) is a member of the tumor necrosis factor (TNF) superfamily and is known for its role in the survival and maturation of B cells. The aim of the study was to evaluate the serum levels of BAFF in patients with AIH and determine its relation to the clinical features of AIH. We examined serum BAFF levels in 55 patients with AIH, 14 patients with acute hepatitis (AH), 33 patients with chronic hepatitis C, and 33 healthy subjects by enzyme-linked immunosorbent assay. Liver function tests, quantitative immunoglobulin, and antinuclear antibody levels were also assayed in AIH patients. Serum BAFF levels were elevated in AIH patients compared with healthy subjects (AIH: 2.07+/-1.21 pg/ml, control: 0.77+/-0.22 pg/ml). Similarly, serum BAFF levels were significantly higher in AIH patients compared with AH or chronic hepatitis C patients. There was a positive correlation between BAFF and aspartate aminotransferase (r=0.513, p<0.0001), alanine aminotransferase (r=0.435, p<0.0001), total bilirubin (r=0.419, p<0.01), and soluble CD30 (r=0.579, p<0.0001) in AIH patients. However, there was no correlation between BAFF and levels of gammaglobulins or titer of antinuclear antibodies. Corticosteroid treatment resulted in marked reduction in serum BAFF levels in AIH patients. These results suggest that BAFF contributes to liver injury and disease development in AIH patients.     

High-Dose Dexamethasone Inhibits BAFF Expression in Patients with Immune Thrombocytopenia

Introduction  B-cell activating factor belonging to the TNF family (BAFF) is elevated in several autoimmune diseases including immune thrombocytopenia (ITP). High-dose dexamethasone (HD-DXM) has shown its clinical efficacy in ITP patients. Materials and Methods  The plasma BAFF concentration and BAFF mRNA were measured in ITP patients before and after oral administration of 40 mg/day DXM for four consecutive days by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR. Moreover, we evaluated the effects of DXM on BAFF expression and proliferation of lymphocytes by ELISA, real-time quantitative PCR and cell proliferation respectively in in vitro experiment. Results  Both plasma BAFF concentration and BAFF mRNA were significantly increased in active ITP patients at pretherapy when compared with controls (P < 0.001). After 4-day treatment with HD-DXM, the BAFF and BAFF mRNA were decreased, and lower than that for controls. In in vitro assays, we found DXM-inhibited BAFF, IFN-γ expression, and the proliferation of lymphocytes in a dose-dependent manner. Conclusion  These results suggest that BAFF expression is increased in ITP patients with active disease, and DXM is an effective inhibitor of BAFF production. As immunosuppressant, DXM may play its role in ITP treatment partly through regulating BAFF expression. Xiao-juan Zhu, Yan Shi, and Jian-zhi Sun contributed equally to this work.     

BAFFled B cells survive and thrive: roles of BAFF in B-cell development

Interactions of BAFF (B-cell activating factor) with BAFF-R, one of three BAFF-binding receptors that are preferentially expressed on B cells, are essential for B-cell development, because defects in either the ligand or the receptor arrest progression from immature type-1 B cells to type-2 cells and mature cells; B1 B cells are unaffected. Transgenic BAFF overexpression leads to B-cell hyperplasia and autoimmune disease. In vitro, BAFF increases survival of immature and mature B cells; immature B cells also mature polyclonally to mature B cells, without proliferation. Upon BAFF-influenced differentiation, immature B cells change their surface-IgM signal transduction machinery and proliferate rather than undergoing apoptosis.     

BAFF maintains T-cell survival by inducing OPN expression in B cells

Dysregulation of T-cell survival and apoptosis is the common cause of autoimmune diseases such as multiple sclerosis (MS). However, the factors inducing imbalance of T-cell survival and apoptosis in MS remains unclear. Here, we show that the resistance to apoptosis was associated with high levels of B-cell activating factor (BAFF). Blockade of BAFF with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor)-IgG significantly reduced T-cell survival in myelin oligodendroglia glycoprotein (MOG)-induced chronic experimental allergic encephalitis (EAE). Furthermore, BAFF induced anti-apoptotic molecule Bcl2 expression in T cells by up-regulating osteopontin (OPN) secretion from B cells. BAFF mainly induced OPN expression in splenic CD21⁻CD23⁺ B cells via a NF-kB dependent signaling pathway. In addition, we found that BAFF and OPN levels were increased in MS patients similar to the results obtained from our mice research. The study suggests that BAFF regulates T-cell survival by inducing OPN secretion in B cells in autoimmune diseases.     

B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling

B-cell activation factor from the tumor necrosis factor family (BAFF) is a key survival factor during B-cell maturation -- a delicate immune checkpoint for B cells. Excessive BAFF production at this stage corrupts B-cell tolerance and leads to autoimmunity. Elevated serum BAFF levels have been detected in some patients suffering from various autoimmune conditions. The positive outcomes of currently ongoing clinical trials using BAFF-neutralising agents confirm that this factor plays a major pathological role in rheumatoid arthritis and in systemic lupus erythematosus. Almost a decade after its discovery, BAFF continues to occupy the main stage in Immunology, with more than one hundred BAFF-related articles published per year. In recent years, our understanding of cell signaling and autoimmune mechanisms in this system have seen major advances, refining new possibilities for therapeutic intervention.     

The role of BAFF in autoimmune diseases]

B cell activating factor belonging to the tumor necrosis factor family (BAFF) is a tumor necrosis factor (TNF) superfamily member best known for its role in the survival and maturation of B cells. BAFF is a ligand for three TNF receptor superfamily members: B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and BAFF receptor (BAFF-R). Among them, BAFF-R plays the central role in the BAFF system, whereas TACI plays the inhibitory role. BAFF/BAFF receptors appear to span nearly all stages of B-lineage differentiation, ranging from the development, selection, and homeostasis of naive primary B cells to the maintenance of long-lived bone marrow plasma cells. Furthermore, excessive BAFF rescues self-reactive B cells from anergy, which may play a crucial role in the induction and development of autoimmunity. Mice overexpressing BAFF exhibit increased B cell numbers in spleen and lymph node and autoimmune phenotype similar to patients with systemic lupus erythematosus (SLE) and Sj?gren's syndrome. Furthermore, inhibition of BAFF by TACI-Ig and BAFFR-Ig has been successful in treating murine models of SLE and rheumatoid arthritis. In humans, previous reports have shown elevated serum BAFF levels in SLE, rheumatoid arthritis, Sj?gren's syndrome, and systemic sclerosis patients. Thus, the dysregulation of BAFF/BAFF receptor system may contribute to induction and development of autoimmune diseases and become one of important therapeutic targets.     

Simultaneous measurement of twenty-nine circulating cytokines and growth factors in female patients with overt autoimmune thyroid diseases

Abstract

Cytokines and growth factors participate in immune responses, and the pathogenesis of autoimmune diseases. Herein, we simultaneously examined differential levels of 29 circulating factors to determine their associations in female patients with overt autoimmune thyroid disease (AITD). We enrolled 40 patients with Graves’ disease (GD), 20 patients with Hashimoto’s thyroiditis (HT), and 14 healthy controls. Twenty-nine circulating factors were simultaneously measured. GD patients with low thyroid-stimulating hormone at the time of sample collection were defined as having active GD. B-cell activating factor (BAFF) levels were associated with GD and HT (p?=?.001 and .001, respectively) and interferon (IFN)-α levels were higher in the HT group than in the control group (p?=?.021). Significant associations of serum BAFF and tumour necrosis factor (TNF)-α levels with free thyroxin (FT4) were present in HT (r = ?0.498, p?=?.026, and r?=?0.544, p?=?.013, respectively). Meanwhile, there were significant associations of FT4 with interleukin (IL)-4 and eotaxin levels in GD (r?=?0.354, p?=?.025 and r?=?0.384, p?=?.014, respectively). In active GD, serum BAFF and eotaxin level were correlated with FT4 levels (r?=?0.465, p?=?.034, and r?=?0.463, p?=?.035, respectively). In conclusion, BAFF is the best circulating indicator to identify GD and HT among all chosen 29 biomarkers, and it could be used to predict the disease severity in HT and active GD. Meanwhile, IFN-α could be another reliable parameter for recognising HT.     

The BAFF/APRIL system in systemic autoimmune diseases with a special emphasis on Sjögren's syndrome

Systemic autoimmune diseases, such as Sjögren's syndrome (SS), are characterized by a complex aetiology with multiple pathogenic factors. In SS, disturbed B-cell biology and humoral immunity including B-cell-activating factor (BAFF)-mediated processes have been described. Dysregulated BAFF expression has been described to lead to disease progression and perpetuation of humoral autoimmunity. Moreover, BAFF has been proposed to contribute to the development of B-cell malignancies. In this review, we summarize the current knowledge on BAFF with regard to SS pathology and discuss special features such as germinal centre (GC) formation and lymphomagenesis. Locally, in SS salivary glands, the reduced level of apoptosis among BAFF-expressing cells might lead to longer-existing BAFF expression and thereby maintain signalling for tissue-infiltrating B cells to proliferate and supposedly to become autoantibody-producing plasma cells. We assume that prolonged BAFF signalization may contribute to GC formation and/or lymphoma development in the disease. Finally, we discuss possibilities of novel treatments targeting the BAFF-system in SS.     

Serum free light chains of immunoglobulins as biomarkers for systemic sclerosis characteristics,activity and severity

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Humoral immunity and B cells are thought to play an important role in the pathophysiology of the disease. B cells are activated, produce specific autoantibodies and profibrotic cytokines. One way to assess B cell activation is to measure serum free light chains of immunoglobulins (sFLC) levels. We assess here sFLC levels in patients with systemic sclerosis (SSc) and their correlation with the disease characteristics, activity and severity. One hundred and thirty-four SSc patients were prospectively enrolled and compared to 401 age- and sex-matched healthy controls. sFLC levels were measured by a new quantitative immunoassay. sFLC levels were significantly higher in SSc patients than in healthy controls. sFLC levels correlated with modified Rodnan skin score and were independently associated with the presence of interstitial lung disease and its severity. In univariate analysis, sFLC levels correlated with SSc activity, as measured by the European Scleroderma Study Group activity index, and severity, as measured by the Medsger's total severity score. In multivariate analysis, beta2-microglobulin levels correlated with disease activity, BAFF levels with severity and sFLC with neither of these. Other B-cell activation biomarkers (IgG, IgA, beta2-microglobulin and BAFF) were independently correlated with sFLC. sFLC levels are elevated in SSc and are independently associated with lung disease and its severity. B-cell activation biomarkers, including sFLC, beta2-microglobulin and BAFF, correlate with disease severity and activity. These results further support the role of B cell activation in the pathophysiology of SSc.     

BAFF,a New Target for Intravenous Immunoglobulin in Autoimmunity and Cancer

Intravenous immunoglobulin (IVIg) has been used to treat autoimmune diseases and lymphoid malignancies with some therapeutic effect. In both these pathological conditions, there is an overproduction of BAFF (for “B-cell-activating factor of the TNF family”), and APRIL (for “a proliferation-inducing ligand”). The presence of antibodies (Abs) with BAFF and APRIL specificities in IVIg preparations was investigated by enzyme-linked immunosorbent assay, and Western Blot analysis. Apoptosis was measured by the annexin-V binding method, and confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique. Nonglycosylated recombinant BAFF, glycosylated affinity-purified BAFF, and recombinant APRIL (but not TNFα), were recognized by certain IgG in IVIg, and their F(ab′)₂ fragments. Steric hindrance prevented the antiapoptotic effects of BAFF on B-lymphocytes. This work documents the presence of anti-BAFF and anti-APRIL Abs in IVIg. These can functionally neutralize the role of BAFF in B-cell survival. These anti-BAFF IgG might amend deleterious effects of BAFF in B-cell-mediated autoimmune diseases.     

A re-evaluation of anti-NA-14 antibodies in patients with primary Sjögren’s syndrome: Significant role of interferon-γ in the production of autoantibodies against NA-14

Novel autoantibodies against nuclear antigen of 14?kDa (NA-14)/Sjögren’s syndrome nuclear antigen-1 (SSNA-1) are predominantly recognized in sera of patients with primary Sjögren’s syndrome (pSS). However, the detailed characteristics of the anti-NA-14 antibody remain unknown. Here, we sought to clarify the characteristics of anti-SSNA-1/NA-14 antibodies and the mechanisms of autoantibody production using sera from patients with connective tissue diseases (including pSS), autoimmune sera reacting with standard autoantigens (SS-A/Ro and/or SS-B/La, ds DNA, Scl-70 and Jo-1), and normal healthy controls (NHCs). Anti-NA-14 antibodies were predominantly recognized in sera from patients with pSS and in autoimmune sera reacting with thSS-A/Ro and/or -SS-B/Lo. Indirect immunofluorescence analysis showed that NA-14 was strongly expressed in mitotic-phase cells. Patients with pSS having anti-NA-14 antibodies exhibited significant elevation of serum IP-10 and BAFF compared to that in patients with pSS without anti-NA-14 antibodies and NHCs. Thus, our data demonstrated that anti-NA-14 antibodies could be classified as novel autoantibodies reacting with mitosis-related autoantigens predominantly recognized in pSS. Moreover, interferon-γ played an important role in the production of anti-NA-14 autoantibodies as patients with pSS having anti-NA-14 antibodies exhibited increased serum levels of IP-10 and BAFF.