APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall2. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs3, but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.

Serum BAFF levels are associated with the prognosis of idiopathic membranous nephropathy.

OBJECTIVE: High serum levels of B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) have been observed in patients with idiopathic membranous nephropathy (iMN); however, their relationships with disease severity and progression remain unclear. METHODS: Patients with iMN diagnosed via renal biopsy were enrolled in this study. The concentrations of BAFF and APRIL were determined using ELISA kits. Proteinuria remission, including complete remission (CR) and partial remission (PR), and renal function deterioration were defined as clinical events. The Cox proportional hazards method was used to analyze the relationship between cytokine levels and disease progression. RESULTS: Seventy iMN patients were enrolled in this study, with a median follow-up time of 24 months (range 6-72 months). The serum levels of BAFF and APRIL were higher in iMN patients than in healthy controls but lower than those in minimal change disease (MCD) patients. The serum BAFF level was positively correlated with the serum APRIL level, serum anti-phospholipase A2 receptor (anti-PLA2R) antibody level, and 24-h proteinuria and negatively correlated with the serum albumin (ALB) level. However, no significant correlation was observed between the serum APRIL level and clinical parameters. According to the multivariate Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), immunosuppressive agent use, 24-h proteinuria, APRIL level, and anti-PLA2R antibody, only the serum BAFF level was identified as an independent predictor of PR (HR, 0.613; 95% CI, 0.405-0.927; p = 0.021) and CR of proteinuria (HR, 0.362; 95% CI, 0.202-0.648; p < 0.001). CONCLUSIONS: A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.

The prognostic value of serum levels of a proliferation-inducing ligand (APRIL) in treatment-naïve patients with chronic lymphocytic leukemia

Background/aim: A proliferation-inducing ligand (APRIL) has been investigated as a prognostic marker in chronic lymphocytic leukemia (CLL) patients. However, there is no cut-off level for serum APRIL (sAPRIL) levels that predict time to treatment in CLL patients. Materials and methods: Between May and December 2012, 94 consecutive CLL patients and 25 healthy controls were assessed. sAPRIL levels were measured by ELISA. Demographic data and prognostic markers were obtained from the patients' files. Treatment-naïve patients were followed up for 6.5 years for any treatment need. Results: Patients were divided into 3 groups: Treatment-naïve (n = 47), chemotherapy receiving (n = 25), and those who had received chemotherapy previously (n = 22). There was no difference in median sAPRIL levels of patients who were receiving chemotherapy at the sampling time and the healthy controls, which indicates that sAPRIL levels might be influenced by treatment. For treatment-naïve patients, the best cut-off in predicting time to treatment was found at the sAPRIL level of 2.04 ng/mL, with 78% sensitivity and 63% specificity. Time to treatment was significantly earlier in the APRIL high group (n = 27) than in the APRIL low group (n = 20) (P = 0.010, log-rank test). Conclusion: sAPRIL, a simple, promising blood test which can be measured by ELISA, will likely obtain a place in the wide range of prognostic markers in CLL. Prospective large-scale studies are required to validate and confirm the feasibility of the proposed cut-off level of 2.04 ng/mL as a predictor of time to treatment in treatment-naïve CLL patients.

Serum a proliferation-inducing ligand and MicroRNA-223 are associated with rheumatoid arthritis: diagnostic and prognostic implications.

BACKGROUND: Current blood-based tests for rheumatoid arthritis (RA) have inherent limitations, necessitating the need for additional new biomarkers for its diagnosis and monitoring disease activity and responsiveness to therapy. MicroRNAs (miRNAs) and a proliferation-inducing ligand (APRIL) are deregulated in RA and were linked to its pathogenesis. This study investigated serum levels of APRIL, miR-223 and miR-155 in RA patients, their potential as diagnostic and prognostic biomarkers, and their correlation with disease activity and clinicopathological data. METHODS: One hundred and twenty Egyptian patients with RA and 130 healthy controls were included. Serum miRNAs and APRIL were assayed by RT-qPCR and ELISA, respectively. RESULTS: Serum APRIL and miR-223 were significantly upregulated, while miR-155 was unchanged in RA patients compared to controls. Serum miR-223 discriminated RA patients from controls with AUC = 0.85, whereas serum APRIL superiorly distinguished the two groups with AUC = 1 (sensitivity and specificity = 100% at cutoff> 4.19 ng/ml) by receiver-operating-characteristic analysis. Serum miR-223 was a significant predictor for RA diagnosis in multivariate logistic regression analysis. In RA group, serum APRIL was positively correlated with disease activity score (DAS28-CRP). Serum miR-223 expression was positively correlated with serum miR-155, APRIL levels and with the presence of subcutaneous nodules. Serum miR-155 levels were correlated with antinuclear antibody titer in reverse direction. CONCLUSION: Our results suggest serum APRIL and miR-223 could serve as potential biomarkers of RA, with miR-223 as a predictor of RA risk and APRIL as an excellent biomarker of disease activity. Our data could be implicated for accurate and blood-based non-invasive diagnosis and prognosis of RA.

A proliferation-inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients.

BACKGROUND: IgA nephropathy (IgAN) may recur in kidney transplant recipients. B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and α-defensins are involved in the pathogenesis of native IgAN; however, their role on IgAN recurrence has not been previously analyzed. METHODS: Thirty-five patients with IgAN who received a kidney transplant in our center between January 1, 1993, and December 31, 2015, were included. Recurrence was diagnosed and ruled out in 14 and 11 patients, respectively, by indication biopsies. Pre-transplant, 6-month, 1-, 3-, and 5-year sera selected to measure BAFF, APRIL, and defensin by ELISA. RESULTS: Six months post-transplantation, APRIL levels (300.1 vs 1203.8 pg/mL, P = 0.033) and the mean APRIL values from 6 months to 3 years (409.8 vs 1258.0 pg/mL, P = 0.003) were higher in recurrent patients. Both 6-month APRIL levels (AUC-ROC 0.753, P = 0.033) and mean APRIL values (AUC-ROC 0.844, P = 0.004) discriminated patients with recurrence risk. By logistic regression, APRIL at 6 months (P = 0.044) and mean APRIL (P = 0.021) related to the risk of IgAN recurrence independently. Neither BAFF nor defensin related to recurrence. CONCLUSIONS: Serum APRIL increased at 6 months and mean APRIL remained higher the first 3 years in patients in whom IgAN was going to recur.

The association of tumor necrosis factor superfamily 13 with recurrence of immunoglobulin A nephropathy in living related kidney transplantation.

BACKGROUND: An increasing amount of evidence has demonstrated an association between an increase in the level of tumor necrosis factor superfamily 13 (TNFSF13) and immunoglobulin A nephropathy (IgAN) progression. We aimed to evaluate if the level of pre-transplant serum TNFSF13 is predictive of IgAN recurrence after kidney transplantation. METHODS: This analysis was based on the clinical and laboratory data of 69 patients with IgAN who underwent first kidney transplantation with no evidence of mesangial IgA deposits in zero-time transplantation biopsy. We measured pre-transplant serum TNFSF13, total IgA, and galactose-deficient IgA1 levels. RESULTS: The recurrence rate of IgAN over a median follow-up duration of 5.1 years was 15.9% (11/69 patients), with a mean time to the first recurrence of 1.7 years. The high pre-transplant TNFSF13 level was associated with IgAN recurrence after kidney transplantation among patients who received a graft from a living related donor. CONCLUSIONS: This study highlights association of TNFSF13 levels in recurrent IgAN patients who undergo living related donor transplantation. Further research is needed to clarify mechanisms by which TNFSF13 affects the recurrence of IgA nephropathy.

Cells, cytokines, chemokines, and cancer stress: A biobehavioral study of patients with chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with profound disease-related cellular, humoral, and innate immune suppression. The objective of this study was to study the correlations between stress and disease-specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL. METHODS: A single-group, observational design was used. Patients with relapsed/refractory CLL (N = 96) who were entering a phase 2 trial of an experimental therapy (ibrutinib) were studied. Before the first dose, a validated self-report measure of stress (the Impact of Event Scale) was completed, and blood was drawn for absolute lymphocyte counts (ALCs) and for cytokine and chemokine enzyme-linked immunosorbent assays. Multiple linear regression models tested stress as a concurrent predictor of ALCs; of cytokines (tumor necrosis factor α [TNFα], a proliferation-inducing ligand [APRIL], B-cell activating factor [BAFF], interleukin 6 [IL-6], IL-10, IL-16, and vascular endothelial growth factor [VEGF]); and of the chemokine (C-C motif) ligand 3 (CCL3). RESULTS: Controlling for relevant demographic variables, comorbidities, CLL genetic risk (deletion of the short arm of chromosome 17 [del17p]), and correlates of inflammation, stress predicted higher ALCs (P < .05), and higher levels of TNFα (P < .05), IL-16 (P < .01), and CCL3 (P < .05). Stress was not associated with APRIL, BAFF, IL-6, IL-10, or VEGF. CONCLUSIONS: Novel biobehavioral data from patients with relapsed/refractory CLL demonstrate that stress is related to heightened levels of cellular, cytokine, and chemokine markers associated previously with progressive disease in CLL. The current results indicate that stress is related to immune and inflammatory processes that contribute to cancer cell proliferation and survival. These data provide a first look into these processes. Cancer 2018. © 2018 American Cancer Society.

Effect of glucocorticoid treatment on BAFF and APRIL expression in patients with immune thrombocytopenia (ITP).

Immune thrombocytopenic purpura (ITP) is an idiopathic bleeding disorder. B cell activating factor (BAFF) and 'A proliferation-inducing ligand' (APRIL) have regulatory effects on B and T cells and may represent relevant factors in the pathogenesis of ITP. Serum levels and gene expression were investigated in ITP patients. Both BAFF and APRIL serum levels were significantly elevated in active ITP. However, gene expression analysis revealed both factors to have a tendency toward downregulation. Glucocorticoid treatment significantly reduced BAFF but not APRIL serum levels, which may be mediated by differences in transcription factor binding sites. The glucocorticoid receptor binding site is present in the BAFF promotor region, but not in the APRIL promotor region. Prednisolone in combination with vitamin D3 may be effective in reducing APRIL serum levels. In conclusion, glucocorticoid treatment exerts different regulatory effects on both BAFF and APRIL, whereas antioxidant supplementation may also be beneficial in reducing serum levels.

The role of TNF-α superfamily members in immunopathogenesis of sepsis.

BACKGROUND: Members of TNFα superfamily, A proliferation inducing ligand (APRIL), B-cell activating factor (BAFF) and Transmembrane activator and calcium cyclophylin interactor (TACI) are main regulators of B-cell function. The aim of this study was to evaluate concentrations of APRIL, BAFF and soluble TACI (sTACI) receptor in septic patients compared to healthy controls and compare concentrations of these biomarkers depending on sepsis severity and outcome. MATERIALS AND METHODS: A total of 115 septic patients and 30 healthy volunteers were included and concentrations of APRIL, BAFF and sTACI were determined in all subjects at the admission (ELISA R&D Systems tests). Concentrations of these biomarkers in function of sepsis severity (sepsis n = 94 and septic shock n = 21) and outcome (lethal n = 40, recovery n = 75) were tested, as well as correlations with APACHE II and SOFA scores, immunoglobulins, complement, PCT and CRP concentrations. RESULTS: Concentrations of all three biomarkers were significantly increased in septic patients compared to controls (AUCAPRIL = 0.982, AUCBAFF = 0.873, AUCsTACI = 0.683). Higher concentrations of APRIL and sTACI (p = 0.033, p = 0.037), and lower concentrations of BAFF (p = 0.005) were observed in patients with septic shock compared to sepsis. BAFF concentrations correlated positively with IgM, C3 and C4 levels. sTACI and APRIL were shown to be predictors of lethal outcome (p = 0.003, p = 0.049). CONCLUSIONS: Concentrations of observedTNFα superfamily members are significantly increased in septic patients, confirming their role in sepsis pathogenesis.Higher concentrations of anti-inflammatory sTACI receptor correlated with severity of sepsis and poorer prognosis, thus potentially indicating domination of anti-inflammatory response in septic patients with worse outcome.

Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus - distinct roles of BAFF and APRIL.

Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/µl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.

Increased BAFF and APRIL levels in the cerebrospinal fluid of patients with anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

Hypertrophic pachymeningitis (HP) is an inflammatory disorder involving intracranial or spinal thickened dura mater. It has been recognized that anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis may lead to HP; however, the immune-mediated pathogenesis of ANCA-related HP (ANCA-HP) remains elusive. In the present study, we analyzed B-cell activation factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) expression in the cerebrospinal fluid (CSF) and serum of patients with ANCA-HP, multiple sclerosis (MS), and non-inflammatory neurological disorders (NIND). BAFF and APRIL levels in the CSF were significantly higher in patients with ANCA-HP than in those with MS and NIND. In addition, a positive correlation between BAFF levels in the CSF and IgG-index was found in patients with ANCA-HP. On the other hand, no correlation was detected between CSF and serum levels of BAFF or APRIL. The results suggest that increased levels of BAFF and APRIL produced in the central nervous system may influence the development of ANCA-HP.

The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy.

TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.

Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus.

OBJECTIVE: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). RESULTS: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). CONCLUSIONS: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients.

The impact of TNF superfamily molecules on overall survival in acute myeloid leukaemia: correlation with biological and clinical features.

B cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis-inducing ligand (TRAIL) were demonstrated in several haematological diseases including acute myeloid leukemia (AML). Those cytokines are capable of activating a broad spectrum of intracellular signalling cascades that can either induce apoptosis or protect from programmed cell death. We have analysed BAFF, APRIL and TRAIL serum concentrations in 76 patients with newly diagnosed AML and 40 healthy volunteers. The values were significantly higher for APRIL and BAFF but lower for TRAIL compared to healthy volunteers. Induction therapy significantly reduced the values for BAFF and increased them for TRAIL. Moreover, the concentration of BAFF and APRIL was significantly lower and the concentration of TRAIL higher in a group of patients with complete remission compared to non-respondent AML patients. In addition, higher concentrations of BAFF and lower of TRAIL predicted a shorter overall survival, suggesting thereby an important prognostic marker and possible therapeutic target in AML.

High APRIL but not BAFF serum levels are associated with poor outcome in patients with follicular lymphoma.

Elevated B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serum levels have been reported to correlate with worse prognosis in B cell-derived malignancies. However, limited information exists regarding the prognostic significance of BAFF and APRIL serum levels in follicular lymphoma (FL). We measured BAFF and APRIL serum levels for 81 patients with newly diagnosed FL and 12 healthy controls. The mean ± standard deviation (SD) BAFF serum level (1,193.86 ± 1,126.51 pg/ml) was higher in patients with FL than that in the controls (477.16 ± 155.55 pg/ml; P < 0.001). No significant difference in the mean ± SD serum level of APRIL was found between patients and healthy controls (14.39 ± 43.33 vs 5.07 ± 2.52 ng/ml; P = 0.193). When the patients were divided into low- and high-BAFF and low- and high-APRIL groups based on the median value of the BAFF and APRIL serum levels (855.14 pg/ml and 6.35 ng/ml, respectively), a high APRIL, but not a high BAFF, serum level significantly correlated with low complete response rate to initial therapy, high relapse/progression rate, and inferior progression-free survival (PFS; P = 0.019) and overall survival (OS; P = 0.008) rates. A high APRIL serum level was also significantly associated with decreased PFS and OS in patients treated with non-rituximab regimens but not in patients treated with rituximab-containing regimens. The APRIL serum level remained an independent predictor for PFS and OS in multivariate analysis. APRIL may be an important prognostic predictor with potential significance as a therapeutic target in FL.

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma.

Tumour necrosis factor alpha (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the TNF-α family. Vascular endothelial growth factor (VEGF), on the other hand, is one of the most characteristic pro-angiogenic cytokines produced by multiple cell types in multiple myeloma (MM). We have analysed BAFF and APRIL concentrations in parallel with pro-angiogenic cytokines in serum and trephine biopsy, and the bone marrow microvascular density (MVD) in 50 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of BAFF, APRIL and TNF-α, as well as VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. A statistically positive correlation between the concentration of TNF-α and the expression of VEGF was demonstrated, and so was a positive link between BAFF, APRIL, MVD and lactate dehydrogenase (LDH). Furthermore, we observed a significant decrease in all studied cytokines after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with stable disease. It was also established that APRIL, but not BAFF, correlated with pro-angiogenic cytokines such as VEGF with its receptor, MVD and syndecan-1. Finally, our results showed that serum BAFF and APRIL levels could be useful biomarkers of MM disease activity and its progression which suggests that APRIL could be a possible novel therapeutic target in MM.

APRIL levels strongly correlate with IL-17 in systemic lupus erythematosus.

INTRODUCTION: Activated self-reactive B cells play an important part in systemic lupus erythematosus (SLE). A proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF) are B-cell specific stimulators, but activate B cells through different receptors. We investigated the reciprocal association between serum APRIL (s-APRIL), serum BAFF (s-BAFF) and immunological and clinical findings in SLE patients. METHODS: A cross-sectional case-control study was performed in 100 SLE patients (87% female, age 49 years, disease duration 12 years). APRIL and BAFF levels were measured by sandwich ELISA, compared with healthy controls and correlated with autoantibody, cytokine (IL-6 and IL-17) and clinical findings through nonparametric and multivariate regression analyses. RESULTS: Both median s-APRIL (478 vs. 0 pg/ml, p = 0.01) and s-BAFF (1720 vs. 0.9 pg/ml, p < 0.001) were higher in SLE patients than controls. Increased s-BAFF was observed in 86% of patients, while s-APRIL was increased only in 17% (p < 0.01). S-APRIL correlated with s-BAFF in controls (p = 0.04), but not in SLE (p = 0.8). Increased s-APRIL was strongly and independently associated with IL-17 activation (p < 0.001), while increased s-BAFF levels were associated with anti-nucleosome antibody presence (p = 0.001). Disease activity and organ damage were associated with s-BAFF but not s-APRIL. CONCLUSIONS: While both s-BAFF and s-APRIL levels are elevated in SLE patients, they reflect different immunologic and clinical pathways. The strong association between s-APRIL and IL-17 activation supports a role for Th17 helper cells in B cell activation in SLE.

The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arthritis.

OBJECTIVES: To determine the differences in a proliferation-inducing ligand (APRIL) between seropositive and seronegative rheumatoid arthritis (RA) patients and further investigate the possible pathogenesis of the two subtypes of RA. METHOD: Concentrations of APRIL in sera (18 seropositive RA patients, 16 seronegative RA patients, and 10 healthy controls) and synovial fluid (SF) (eight seropositive RA patients, two seronegative RA patients, and 10 controls) were detected by enzyme-linked immunosorbent assay (ELISA). Infiltration of plasma cells, macrophages, and APRIL-positive cells in the synovium [14 seropositives, eight seronegatives, and 10 osteoarthritis (OA) controls] was detected by immunohistochemistry. Correlations between serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 28-joint Disease Activity Score (DAS28), and sera/SF levels of APRIL and synovial cell infiltration were analysed. RESULTS: The mean serum APRIL level of seropositive RA patients was significantly higher than that of seronegative patients (26.1 ± 31.2 vs. 8.0 ± 10.2 ng/mL, p = 0.03). The level of APRIL in the SF of seropositive RA patients was comparable to that of seronegative patients [47.9 ± 54.4 vs. 32.82 (6.52-59.12) ng/mL, p > 0.05]. The SF APRIL level of RA patients was higher than that of patients with other inflammatory arthritis. Dramatically increased infiltration of APRIL-positive cells in the RA synovium was observed compared with the OA group (seropositive RA vs. OA, p < 0.001; seronegative RA vs. OA, p = 0.001). The infiltration of both plasma cells and macrophages was more in seropositive RA than in OA (p = 0.013 and p = 0.003, respectively). CONCLUSIONS: The serum APRIL levels of seropositive RA patients are significantly higher than those of seronegative RA patients. APRIL may participate in the formation of seropositive RA.

Raised expression of APRIL in Chinese children with acute lymphoblastic leukemia and its clinical implications.

This study was to determine the expression of a proliferation-inducing ligand (APRIL) and its receptors, B-cell maturation antigen (BCMA) and transmembrane activator and calcium-modulating cyclophilin ligand interactor in childhood acute lymphoblastic leukemia (ALL). The correlation between the plasma APRIL levels and clinical status was also evaluated. Plasma samples from 20 untreated children with ALL, 23 children with ALL in remission, and 15 normal controls were assayed for APRIL plasma concentration by enzyme-linked immunosorbent assay. Real-time quantitative polymerase chain reaction was performed to determine the mRNA expression of APRIL and its receptors in blood mononuclear cells in 20 untreated ALL children and 15 normal controls. The untreated ALL patients had higher plasma APRIL levels than the remission group and the normal controls (P<0.001, respectively). No significant difference was found between the remission group and the normal controls in the plasma APRIL levels (P=0.339). The plasma APRIL levels in the untreated patients correlated with white blood cell count at diagnosis (P=0.002) and risk category (P=0.013). The mRNA expression of both APRIL and BCMA in blood mononuclear cells of the ALL patients were higher than those of the normal controls (both P<0.001). No significant difference was found between the patients and the normal controls in the transmembrane activator and calcium-modulating cyclophilin ligand interactor expression (P>0.05). These findings indicate that APRIL and BCMA are over expressed in untreated ALL children. The levels of APRIL correlate with the progression of childhood ALL, which may provide certain clues for monitoring ALL clinically.

TNF superfamily proteins in the serum of patients with B-ALL--preliminary study.

BACKGROUND: TNF superfamily ligands such as B cell-activating factor (BAFF), a proliferation inducing ligand (APRIL) and TNF-related apoptosis inducing ligand (TRAIL), can play an important role in the pathogenesis and development of various B cell malignancies involving B-ALL. METHODS: The study group consisted of 25 children suffering from newly diagnosed B cell precursor ALL (B- ALL), involving immunophenotype pre-B and common-cALL. Peripheral blood samples were collected at the time of diagnosis, before any treatment, and after treatment. Soluble APRIL, soluble BAFF, and soluble TRAIL concentrations were assessed using ELISA kits. RESULTS: The concentrations of sAPRIL and sBAFF in the sera of the patient group were higher compared to the values of the control specimens. Among all molecules examined, the highest concentrations were found for the sAPRIL molecule. Furthermore, sAPRIL and sBAFF concentrations were higher in patients with ALL-pre B than in patients with cALL. After the treatment, the sera of patients with ALL-pre B contained lower concentrations of sAPRIL, sBAFF, and sTRAIL than those of the same patients before therapy. CONCLUSIONS: Contrary to earlier indications of the key function of BAFF in B-ALL, the quantitative dominance of APRIL in the serum suggests that this molecule can play an equivalent or even more significant role in this patient group than BAFF.