A Proliferation-inducing Ligand Levels Research Articles

Influence of B cells in liver fibrosis associated with hepatitis B virus harboring basal core promoter mutations

The development of the liver disease in chronic hepatitis B with common viral variants can be determined through the interaction between the virus and the host immune response. B cells constitute half of the intrahepatic lymphocyte population with an impact on fibrosis. A proliferation-inducing ligand (APRIL) has been shown to have a co-stimulatory activity on B cells. For this study HBV DNA was amplified and then sequenced to show the presence of the basal core promoter (BCP) mutations in the serum from 57 patients with chronic hepatitis B. The range of IgD-positive B cells was detected by immunohistochemistry in liver biopsies; and patients serum was assayed for APRIL levels by enzyme immunoassay. Twenty-seven patients (47.4%) harbored the A1762T-G1764A BCP mutations. Coefficients of logistic regression showed that the effect of increasing IgD-positive B cells in rising odds of the liver disease is the same in the patients with BCP mutation A1762T-G1764A and in the patients without mutation, nevertheless the effect of APRIL is not similar in these two groups of patients. Logistic regression in patients with BCP A1762T-G1764A mutations demonstrated that increasing one score of APRIL decreased the odds of fibrosis stage about 8%. These results suggest that in infection with viral variants of hepatitis B virus, the population of IgD-positive B cells may play a decisive role in later stages of the liver disease which is reduced by APRIL in chronic hepatitis patients with BCP mutations.

Serum level of APRIL/BLyS in Behçet’s disease patients: clinical significance in uveitis and disease activity

The aim of the study reported here was to assess the serum concentration of B-cell activating factors, B lymphocyte stimulators (BLyS), and a proliferation-inducing ligand (APRIL) in Behçet disease (BD) patients in order to evaluate their role and study their relation to uveitis subtype and disease activity. The study included 58 consecutively recruited BD patients with a mean age of 35.54 ± 8.85 years and disease duration of 8.33 ± 5.84 years and 30 age- and sex-matched controls. Disease activity was assessed using the BD current activity form score. Patients were subclassified according to the presence and type of uveitis. Serum BLyS and APRIL were measured by enzyme-linked immunosorbent assay. Recurrent uveitis was present in 42 (72.41 %) patients, of whom 19 had the anterior form, 13 had the posterior form, and ten had a combined anterior with posterior form; 16 had no eye involvement. Serum APRIL (60.29 ± 57.99 ng/ml) and BLyS (2.31 ± 1.97 ng/ml) levels were significantly higher in the BD patients than in the controls (4.14 ± 4.31 and 0.49 ± 0.39 ng/ml, respectively; P < 0.0001). The levels were clearly higher in those with combined uveitis. The BLyS level significantly correlated with disease activity. The overexpression of BLyS and APRIL in BD patients supports the notion of a critical role for B cell activation factors in BD, particularly in terms of uveitis and disease activity. This provides an interesting prospect for the use of anti-BLyS/APRIL antibodies against future therapeutic targets.

Increased Levels of BAFF and APRIL Related to Human Active Pulmonary Tuberculosis

BackgroundDespite great efforts to improve diagnosis and treatment, tuberculosis (TB) remains a major health problem worldwide, especially in developing countries. Lack of concrete immune markers is still the obstacle to properly evaluate active TB. Therefore, identification of more validated biomarkers and phenotypic signatures is imperative. In particular, T cell-related biomarkers are more significant.MethodologyTo understand the nature of CD4+ T cell-derived signatures involved in infection and disease development, we examined and analyzed whole genome expression profiles of purified CD4+ T cells from healthy individuals (HD), two distinct populations with latent infection (with low or high IFN-γ levels, LTBL/LTBH) and untreated TB patients. Following, we validated the expression profiles of genes in the peripheral CD4+ T cells from each group and examined secretion levels of distinct cytokines in serum and pleural effusion.Principal FindingsOur bio-informatic analyses indicate that the two latent populations and clinical TB patients possess distinct CD4+ T cell gene expression profiles. Furthermore, The mRNA and protein expression levels of B cell activating factor (BAFF), which belongs to the TNF family, and a proliferation-inducing ligand (APRIL) were markedly up-regulated at the disease stage. In particular, the dramatic enhancement of BAFF and APRIL in the pleural effusion of patients with tuberculosis pleurisy suggests that these proteins may present disease status. In addition, we found that the BAFF/APRIL system was closely related to the Th1 immune response. Our study delineates previously unreported roles of BAFF and APRIL in the development of tuberculosis, and these findings have implications for the diagnosis of the disease. Our study also identifies a number of transcriptional signatures in CD4+ T cells that have the potential to be utilized as diagnostic and prognostic tools to combat the tuberculosis epidemic.

Cerebrospinal Fluid BAFF and APRIL Levels in Neuromyelitis Optica and Multiple Sclerosis Patients During Relapse

BAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) are two of the major survival factors for B cells. Many studies have shown that BAFF levels were elevated in MS patients. However, whether the levels of CSF BAFF/APRIL increased in NMO patients was still unclear. To measure the CSF BAFF and APRIL concentration of in NMO patients, and explore their relationship with disease activity in NMO. CSF BAFF and APRIL was measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n = 22), MS (n = 18) patients and controls (n = 14). Concentration of BAFF and APRIL in NMO patients were significantly higher than MS and controls. CSF BAFF and APRIL levels in controls were also lower than MS. Both NMO and MS revealed an increased disease disability with increased CSF BAFF. CSF APRIL was associated with EDSS scores in NMO, but not found in MS. BAFF/APRIL system considered important for aggressive B cells and T-cell responses, and may stimulates B cells and T cell activation in acute relapse of NMO and MS. In NMO patients, CSF BAFF and APRIL may be key factors of B cell immune response and reflect disease severity.

The expression of APRIL in Sjögren’s syndrome: aberrant expression of APRIL in the salivary gland

A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are B-cell-related mediators and may play a role in the pathogenesis in SS. In this descriptive study we assessed the expression of APRIL and BAFF in the minor salivary gland and serum from SS patients. Paraffin-embedded minor salivary gland sections from SS patients, non-SS controls and healthy volunteers were analysed by immunohistochemistry. Digital image quantification was performed to evaluate the expression of BAFF, APRIL and transmembrane activator and CAML interactor. Furthermore, serum was analysed for soluble BAFF and APRIL levels by ELISA. All the data were also analysed for subjects with decreased and normal stimulated salivary flow independent of the classification. APRIL expression was lower in minor salivary gland biopsies from SS patients compared with healthy volunteers and to a lesser extent non-SS controls, whereas BAFF expression was similar in all groups. Soluble APRIL levels in serum were increased in SS patients and in subjects with decreased salivary flow independent of the classification. APRIL salivary gland tissue levels are decreased, suggesting that targeting this cytokine locally in the salivary glands would not benefit SS patients. Moreover, the discrepancy between local and systemic levels is striking and future research should assess this in more detail.

Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance

IntroductionB cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) play a crucial role in B cell development, survival, and antibody production. Here we analyzed the serum levels of BAFF and APRIL and their respective clinical associations in patients with an immunoglobulin (Ig) G4-related disease (IgG4-RD).MethodsWe measured serum levels of BAFF and APRIL in patients with IgG4-RD, primary Sjögren's syndrome (pSS), and healthy individuals. Serum BAFF and APRIL levels in IgG4-RD were assessed for correlations with serological parameters, including Ig, particularly IgG4, and the number of affected organs. Serum BAFF and APRIL levels in IgG4-RD were monitored during glucocorticoid (GC) therapy.ResultsSerum BAFF and APRIL levels in patients with IgG4-RD were significantly higher (P < 0.01) than in healthy individuals. The BAFF levels of patients with IgG4-RD were comparable to those of patients with pSS. Although clinical parameters, such as serum IgG4 and the number of affected organs, were not correlated with the levels of BAFF, serum APRIL levels were inversely correlated with serum IgG4 levels (r = -0.626, P < 0.05). While serum BAFF levels decreased following GC therapy, serum APRIL levels increased during follow-up.ConclusionThese results indicate that BAFF and APRIL might be useful markers for predicting disease activity in IgG4-RD. Further studies are needed to elucidate the role of BAFF and APRIL in the pathogenesis of IgG4-RD.

RETRACTED ARTICLE: Targeting of colorectal cancer growth, metastasis, and anti-apoptosis in BALB/c nude mice via APRIL siRNA

A proliferation-inducing ligand (APRIL) is overexpressed in most tumor cells and tissues, especially in tumors of the alimentary system, such as colorectal cancer (CRC), gastric cancer, and liver cancer. RNA interference (RNAi) has been proved to be a powerful tool for gene knockdown and holds great promise for the treatment of cancer. In this study, the efficacy of RNAi targeting APRIL was analyzed via relevant experiments on human CRC xenografted in BALB/c nude mice. Both the mRNA and protein levels of APRIL were examined after intratumoral injection of APRIL small interfering RNA (siRNA). Meanwhile, pathological tools were utilized to observe the alterations on the aspects of proliferation, metastasis, apoptosis and cellular necrosis by means of detecting proliferating cell nuclear antigen, Ki-67, MMP-2, MMP-9, TIMP-3, TIMP-4, Bcl-2, Bax and Bcl-xL of CRC. In addition, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) and hematoxylin and eosin staining were also conducted to examine cell apoptosis and necrosis. It was found that grafted human colorectal tumor growth and metastasis were obviously inhibited while tumor cell apoptosis and necrosis were induced after in vivo APRIL siRNA injection into nude mice. The data indicated that silencing of the APRIL gene using RNAi may serve as a novel therapeutic strategy for treatment of CRC.

TACI-Ig induces immune balance of Th cells in MLN via BLyS/APRIL-receptors signaling in rats with adjuvant-induced arthritis

The transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig), a recombinant fusion protein that modulates B and T cells activation by binding and neutralizing B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), has been shown to have a therapeutic effects on autoimmune disorders. The objective of this study was to investigate immunoregulatory efficacy of TACI-Ig on helper T (Th) cells in mesenteric lymph node (MLN) of adjuvant-induced arthritis (AA) in rats. The levels of BLyS, APRIL, interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor beta (TGF)-β1, and IL-17 were measured by enzyme-linked immunosorbent assay. The localization and expression of TACI, B-cell maturation antigen (BCMA) and B cell activating factor-receptor (BAFF-R) were investigated by immunohistochemistry and western blotting analysis in MLN. Administration of TACI-Ig significantly reduced histological changes, along with decreased Th1 and Th17-cell cytokines and increased CD4+CD25+FOXP3+ regulatory T cell (Treg) and Th2-cell cytokines in MLN of AA rats. The levels of BLyS and APRIL were decreased in MLN homogenate of AA rats after treatment with TACI-Ig. TACI-Ig inhibited TACI and BCMA expression, and increased BAFF-R expression in MLN with AA rats. Taken together, BLyS/APRIL-receptors signaling are important not only for B cell function but for T cell-mediated immune responses. TACI-Ig might exert its anti-inflammatory and immunoregulatory effects through inducing immune balance of Th1/Th2 and Treg/Th17 in peripheral MLN. The mechanisms of TACI-Ig on BLyS/APRIL-receptors-dependent signaling in MLN lymphocytes may play key roles in the pathogenesis of autoimmune disorders.

The Expression of BAFF, APRIL and TWEAK Is Altered in Eczema Skin but Not in the Circulation of Atopic and Seborrheic Eczema Patients

The TNF family cytokines BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand) are crucial survival factors for B-cell development and activation. B-cell directed treatments have been shown to improve atopic eczema (AE), suggesting the involvement of these cytokines in the pathogenesis of AE. We therefore analyzed the expression of these TNF cytokines in AE, seborrheic eczema (SE) and healthy controls (HC). The serum/plasma concentration of BAFF, APRIL and a close TNF member TWEAK (TNF-like weak inducer of apoptosis) was measured by ELISA. The expression of these cytokines and their receptors in skin was analyzed by quantitative RT-PCR and immunofluorescence. Unlike other inflammatory diseases including autoimmune diseases and asthma, the circulating levels of BAFF, APRIL and TWEAK were not elevated in AE or SE patients compared with HCs and did not correlate with the disease severity or systemic IgE levels in AE patients. Interestingly, we found that the expression of these cytokines and their receptors was altered in positive atopy patch test reactions in AE patients (APT-AE) and in lesional skin of AE and SE patients. The expression of APRIL was decreased and the expression of BAFF was increased in eczema skin of AE and SE, which could contribute to a reduced negative regulatory input on B-cells. This was found to be more pronounced in APT-AE, the initiating acute stage of AE, which may result in dysregulation of over-activated B-cells. Furthermore, the expression levels of TWEAK and its receptor positively correlated to each other in SE lesions, but inversely correlated in AE lesions. These results shed light on potential pathogenic roles of these TNF factors in AE and SE, and pinpoint a potential of tailored treatments towards these factors in AE and SE.

Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients

Mechanisms underlying the failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood. To investigate innate immune factors regulating B-cell function in HIV-infected persons and to correlate them with serologic responses to H1N1/09 vaccine. We evaluated immunologic characteristics of 17 HIV-infected patients and 8 healthy controls (HCs) at 0, 7, and 28 days (designated T0, T1, and T2) following a single 15-μg dose of nonadjuvanted H1N1/09 influenza vaccine by using flow cytometry, ELISpot, and ELISA. All HCs and 9 patients (53%) seroconverted with >1:40 hemagglutination inhibition antibody titer at T2. In vaccine responders and HCs, serum levels of BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) increased from T0 to T2 in conjunction with increases in frequencies of memory B cells. Concurrently, receptors for these factors showed changes, with increases in expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and decreases in BAFF receptor in memory B cells. IL-2 secreting cells and IgG antibody-secreting cells increased at T2 in vaccine responders and HCs in exvivo H1N1 antigen-stimulated cultures. These immunologic responses were not evident at T1 and were deficient in vaccine nonresponder patients at T2. At T0, vaccine nonresponders had lower frequencies of BAFF receptor and TACI-expressing memory B cells than did responders. Impaired memory B-cell responses, deficiencies in serum BAFF and APRIL, and alterations in their receptors on B cells were associated with failure of H1N1/09 influenza vaccine responses among virologically controlled HIV-infected patients.

Combined analysis of levels of serum B-cell activating factor and a proliferation-inducing ligand as predictor of disease progression in patients with chronic lymphocytic leukemia

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are regulators of normal B-cell development and survival. We investigated their role in chronic lymphocyticleukemia (CLL) by relating serum protein levels and CLL cell mRNA expression with clinical factors and disease progression. In patients with CLL, BAFF serum levels were significantly lower than in controls (0.64 ng/mL vs. 0.77 ng/mL, p = 0.014), and APRIL serum levels were significantly higher (4.10 ng/mL vs. 1.84 ng/mL, p = 0.041). CLL cells expressed BAFF and APRIL mRNA at lower levels than normal B-cells. Low BAFF serum levels were significantly correlated with a high blood lymphocyte count and advanced clinical stage, whereas APRIL levels were correlated with CD38 expression. In a multivariate analysis, the combined analysis of BAFF and APRIL serum levels emerged as an independent predictor of disease progression.

Serum Levels of B-Cell Activating Factor of TNF Family (BAFF) as a Useful Indicator for the Activity of Graves' Disease

Background : Graves’ disease (GD) is a thyroid-specific autoimmune disorder. Both B-cell activating factor of TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are cytokines which share a role for regulating survival and proliferation of B lymphocytes. Elevated level of these cytokines in circulation was observed in several types of autoimmune diseases. However, there were no reports focusing on the potential relationship between BAFF and the activity of GD. To explore the pathophysiologic role of BAFF and APRIL in GD, we investigated serum levels of BAFF and APRIL in patients with GD. Methods : We enrolled twenty three patients newly diagnosed as GD and twenty healthy donors as controls. We measured serum levels of BAFF and APRIL in patients and controls by ELISA. Results : Serum level of BAFF was significantly elevated in patients with GD compared to controls (1329 + 435 pg/mL vs. 983 + 308 pg/mL, P Conclusions : Findings in the present study offer a novel opportunity to evaluate GD. doi:10.4021/jem16w

Cerebrospinal fluid levels of a proliferation-inducing ligand (APRIL) are increased in patients with neuropsychiatric systemic lupus erythematosus

Objectives: A proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are B-cell stimulation and survival molecules. We have investigated whether APRIL and/or BAFF activity is enhanced in the systemic and/or intrathechal compartment of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). In particular, the association between fatigue and APRIL/BAFF activity was investigated.Methods: Twenty-eight NPSLE patients were evaluated clinically, with sampling of cerebrospinal fluid (CSF) and blood, and magnetic resonance imaging (MRI). CSF and blood samples from 13 multiple sclerosis (MS) patients and 17 patients with other neurological diseases (OND) were used as controls. Protein levels of BAFF and APRIL were quantified in CSF and plasma, mRNA expression levels of BAFF and APRIL were determined in peripheral blood (PBMC) and CSF mononuclear cells (CSF-MC). The Fatigue Severity Scale (FSS) was used to quantify the degree of fatigue.Results: NPSLE patients had higher levels of APRIL in CSF as compared to OND (p < 0.01). No corresponding increase in APRIL mRNA levels was detected in CSF-MC. BAFF levels in plasma were higher in NPSLE than in OND (p < 0.001). BAFF mRNA expression in PBMC was also higher in NPSLE patients than in controls (p < 0.05). FSS scores in patients with NPSLE correlated significantly with APRIL levels in CSF.Conclusions: Protein levels of APRIL in CSF were increased in NPSLE as compared to OND. Moreover, there was a positive correlation between CSF APRIL levels and fatigue. Our results suggest that APRIL and possibly also BAFF may be involved in the pathogenesis of NPSLE and in SLE-related fatigue.

Serum Levels of BAFF and APRIL in Myeloperoxidase Anti-Neutrophil Cytoplasmic Autoantibody-Associated Renal Vasculitis: Association with Disease Activity

Background: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis. Methods: APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications. Results: Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001). Conclusion: Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.

The role of B cells in acute graft-versus-host disease

TO THE EDITOR: Mounting evidences implicates B cells in the pathogenesis of chronic graft-versus-host disease (GVHD). The body of evidence includes findings such as correlation between chronic GVHD and antibody production against Y chromosome-encoded minor histocompatabilty antigens (mHA) generated after sex-mismatched allogeneic stem cell transplantation (SCT), the clinical response of steroid-refractory chronic GVHD to rituximab, and association between high serum B cell-activating factor (BAFF) levels and chronic GVHD [1]. However, the role of B cells in acute GVHD remains controversial. Some studies that showed the association of high B cell count in the grafts in SCT patients with acute GVHD and beneficial effects of rituximab (used for B cell lymphoma treatment before transplantation) in acute GVHD patients, have suggested the possible role of B cells in the development of acute GVHD. Kim et al. reported that the BAFF level/absolute lymphocyte count (ALC) ratio or that of APRIL (a proliferation-inducing ligand) level/ALC at the time of acute GVHD diagnosis was associated with disease severity [2]. In their study, patients with grade III-IV acute GVHD (6) had higher BAFF level/ALC or APRIL level/ALC ratio than the corresponding ratio observed in patients with grade II acute GVHD (9). These findings suggest that BAFF level/ALC or APRIL level/ALC ratio can help determine the severity of acute GVHD and need to be confirmed in large prospective studies. However, it would be somewhat unreasonable to conclude that B cells may play an important role in the development of acute GVHD on the basis of these findings alone. First, counting the number of B cells should be performed along with measurement of the BAFF or APRIL levels because higher serum BAFF levels may reflect relative B lymphopenia depending on the period after transplantation. Furthermore, comparison of the findings for patients with and without acute GVHD for the same period after allogeneic SCT is essential for investigating the relationship between B cells and acute GVHD. BAFF has a complex, dichotomous role in immunity, which is mediated by the differential regulation of T cell- and B cell-dependent immune responses [3]. BAFF, a critical regulator of normal B cell homeostasis in mice and humans, also promotes T cell activation and survival [4]; these T cells play a pivotal role in acute GVHD pathogenesis. However, recent studies have also demonstrated the negative regulatory role of BAFF in T cell function [3, 5]. Walters et al. found that BAFF-transgenic mice accepted islet allografts and showed delayed rejection of skin allografts. On the basis of these results, they proposed that BAFF plays an anti-inflammatory role in T cell biology by promoting the expansion of regulatory T cells [3]. We studied the potential protective effect of BAFF against acute GVHD during the peritransplantation period in the setting of allogeneic SCT in humans [5]. Thus, further experimental and clinical studies are needed to elucidate the role of B cells in the development of acute GVHD and gain more insight into the pathogenesis of acute GVHD by studying the association of BAFF with B cells and T cells.

Cytokine pattern in very early rheumatoid arthritis favours B-cell activation and survival

B cells play an important role in the perpetuation of RA, particularly as autoantibody-producing cells. The ICs that further develop deposit in the joints and aggravate the inflammatory process. However, B-cell contribution in the very early stage of the disease remains unknown. The main goal of this work was to determine the concentration of cytokines potentially relevant for B-cell activation in serum from very early polyarthritis patients, with <6 weeks of disease duration, who latter on evolved into very early RA (VERA). A proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF) and IL-21 levels were measured by ELISA in the serum of VERA, other very early arthritis (VEA), established RA patients and controls. SF samples of established RA were also analysed. VERA patients have higher levels of APRIL and BAFF as compared with VEA, established RA and controls. Furthermore, APRIL and BAFF levels are also significantly elevated in RA-SF when compared with serum. The increased levels of APRIL and BAFF in VERA patients suggests that B-cell activation and the development of autoreactive B-cell responses might be crucial in early phases of RA. Therefore, APRIL and BAFF could be promising targets for therapy in the early phase of RA.

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

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

Alteration in serum B cell‐activating factor levels inpatients with idiopathic thrombocytopenic purpura after Helicobacter pylori eradication therapy

Alteration in serum B cell‐activating factor levels inpatients with idiopathic thrombocytopenic purpura after <i>Helicobacter pylori</i> eradication therapy

Increased Production of a Proliferation-inducing Ligand (APRIL) by Peripheral Blood Mononuclear Cells Is Associated with Antitopoisomerase I Antibody and More Severe Disease in Systemic Sclerosis

A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) family, plays a crucial role in the survival of peripheral B cells, and may contribute to the pathogenesis of systemic sclerosis (SSc) through upregulation of autoantibody production and maintenance of autoimmune phenomena. We evaluated the capacity of peripheral blood mononuclear cells from patients with SSc (SSc-PBMC) to produce APRIL; and investigated correlations between production of APRIL by SSc-PBMC and clinical and laboratory features of the disease. PBMC from 20 patients with SSc and 14 healthy subjects were incubated in fetal calf serum-supplemented RPMI medium. APRIL levels were determined in cell culture supernatants by ELISA. PBMC from patients with SSc produced significantly more APRIL (961 ± 151 pg/ml/10⁵ cells) than control PBMC (798 ± 219 pg/ml/10⁵ cells; p < 0.01). In patients with SSc, increased production of APRIL was associated with the presence of diffuse skin involvement, scleroderma lung disease, peripheral vasculopathy, greater capillary damage on capillaroscopy, and presence of anti-topoisomerase I (anti-topo I) antibodies. Multivariate regression analysis revealed anti-topo I antibodies as the only independent predictor of high production of APRIL by PBMC. Production of APRIL is increased in SSc-PBMC and is associated with the presence of anti-topo I antibodies and more severe disease. Targeting the APRIL pathway might represent a therapeutic possibility for treatment of patients with SSc, in particular those with anti-topo I antibodies.

Elevated serum levels of a proliferation-inducing ligand in patients with systemic sclerosis: Possible association with myositis?

Objective A proliferation-inducing ligand (APRIL) is a new member of the tumour necrosis factor family which is intimately connected to the regulation of cellular pathways. The aim of this study was to assess serum concentrations of APRIL in systemic sclerosis patients, and to correlate them with the main clinical and serological features of the disease. Methods Sera from 35 patients with systemic sclerosis, 25 had limited cutaneous and 10 had diffuse cutaneous subtypes, and 35 normal healthy subjects were assayed for APRIL by Enzyme Linked Immunosorbant Assay. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Results Serum APRIL concentrations were higher in patients with systemic sclerosis and in both its subtypes compared to the healthy controls ( p < 0.0001 in all). Patients with elevated APRIL levels had significantly higher incidences of myositis than those with normal levels ( p = 0.04). We did not find significant differences in other organ involvement prevalence between systemic sclerosis patients with elevated vs. normal APRIL levels. In addition, the frequencies of autoantibodies (i.e., anti-topoisomerase I, anti-centromere) were comparable between both groups. Serum APRIL levels were correlated with serum γ-globulins concentrations ( r = 0.404, p = 0.016) but not with C-reactive protein, skin score, nor pulmonary functions. Serum APRIL was also correlated with creatine kinase levels only in systemic sclerosis patients with myositis ( r = 0.786, p = 0.02). Conclusion Our preliminary results suggest increased serum APRIL levels in systemic sclerosis patients, particularly in those associated with myositis and hypergammaglobinemia. To confirm our results, we propose that larger scale, multicentre studies with longer evaluation periods are needed.