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.

BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy.

BACKGROUND: B-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder. OBJECTIVE: To assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS. METHODS: Soluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally. RESULTS: The mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (-61%) or corticosteroids (-38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into 'high' versus 'normal' CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003). CONCLUSIONS: Striking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.

Cerebrospinal fluid BAFF and APRIL levels in neuromyelitis optica and multiple sclerosis patients during relapse.

BACKGROUND: 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. OBJECTIVE: To measure the CSF BAFF and APRIL concentration of in NMO patients, and explore their relationship with disease activity in NMO. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

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.

Cerebrospinal fluid biomarkers implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

OBJECTIVE: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers related to the pathogenesis of ANCA-related HP (ANCA-HP). METHODS: The levels of B cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-ß1) in the CSF were compared between patients with ANCA-HP (n = 12), other types of immune-mediated HP (other HP; n = 12), multiple sclerosis (MS; n = 14), and non-inflammatory neurological disorders (NIND; n = 10). In addition, we evaluated whether ANCA would be detected in CSF. RESULTS: CSF levels of BAFF, APRIL, and TGF-ß1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive. CONCLUSION: The levels of BAFF, APRIL, and TGF-ß1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting MPO- or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.Key Points• CSF BAFF, APRIL, and TGF-ß1 levels increase significantly in immune-mediated HP.• CSF BAFF and APRIL levels are significantly correlated with IgG index in ANCA-HP.• Detection of MPO- or PR3-ANCA in the CSF is found in some patients with ANCA-HP.• BAFF, APRIL, and ANCA in the CSF may be implicated in the pathogenesis of ANCA-HP.

Alteration of BAFF and APRIL in the cerebrospinal fluid based on the therapeutic response in primary central nervous system B-cell lymphoma.

We evaluated the cerebrospinal fluid (CSF) levels of the B-cell activating factor of the tumor necrosis factor family (BAFF) and A proliferation-inducing ligand (APRIL) in two cases of primary central nervous system B-cell lymphoma (PCNSBL) before and after treatment. One patient achieved clinical remission, and demonstrated decrease in the CSF levels of both BAFF and APRIL after treatment. Meanwhile, the other patient with insufficient therapeutic response showed increase in the BAFF levels despite decrease in APRIL levels. This report suggests that the combination of BAFF and APRIL levels could be useful in estimating the therapeutic efficacy in treating PCNSBL as reliable CSF markers.

Raised cerebrospinal fluid BAFF and APRIL levels in anti-N-methyl-d-aspartate receptor encephalitis: Correlation with clinical outcome.

In this study, we aimed to assess the levels of B cell activating factor from the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in cerebrospinal fluid (CSF) of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and determine their correlation with clinical outcome. BAFF and APRIL concentrations in CSF and serum from 40 patients with anti-NMDAR encephalitis and 20 controls were measured by enzyme-linked immunosorbent assay (ELISA). Compared with controls, the levels of both BAFF and APRIL in CSF were significantly increased in patients with anti-NMDAR encephalitis (p<0.001 and p<0.001). Patients with unfavorable outcome had higher levels of BAFF and APRIL in CSF than those who had favorable outcome (p<0.05 and p<0.05). BAFF and APRIL levels in CSF were elevated and associated with clinical outcome in patients with anti-NMDAR encephalitis, indicating that they may be valuable biomarkers to this disease.

B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) levels in cerebrospinal fluid of patients with meningoencephalitis.

The B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) are important factors for the survival of transitional and mature B cells. High levels of BAFF and APRIL are present in adults with several autoimmune diseases. However, there are few reports about BAFF and APRIL levels in the cerebrospinal fluid (CSF) of patients with meningoencephalitis. We evaluated BAFF and APRIL levels in CSF samples from patients with viral meningitis (VM) (28 patients), autoimmune encephalitis (AE) associated with antineuronal antibodies (15 patients), idiopathic normal pressure hydrocephalus (iNPH) (11 patients), herpes simplex encephalitis (HSE) (9 patients), bacterial meningitis (BM) (6 patients), and cryptococcal meningitis (CM) (4 patients). The CSF BAFF levels were significantly higher in patients with HSE, BM, or VM than AE or iNPH, and significantly higher in patients with CM than iNPH. The CSF APRIL levels were significantly higher in patients with HSE or BM than AE, VM, or iNPH. Although this is a preliminary report due to within-group variation and small sample size, the data suggest that CSF BAFF and APRIL levels are increased in HSE and BM, but not AE.

Cerebrospinal fluid levels of BAFF and APRIL in untreated multiple sclerosis.

OBJECTIVE AND SUBJECTS: To examine in vivo levels of BAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) in both the cerebrospinal fluid (CSF) and serum of 30 naïve MS patients and 79 subjects affected by acute or chronic inflammatory or non-inflammatory neurological diseases. DESIGN: Case-control study. RESULTS: No difference among groups was evidenced in serum BAFF or APRIL levels. By contrast, CSF levels of BAFF in MS (mean 144.3 pg/ml+/-141.2), although not significantly different from those observed in NIND (164.2 pg/ml+/-92.0), acute peripheral OIND (243.1 pg/ml+/-139.0) or chronic OIND (240.2 pg/ml+/-122.5), were significantly higher in acute central OIND patients (1274.0 pg/ml+/-803.8; p<0.001 vs. all groups). Similarly, CSF APRIL levels in MS (1541.0 pg/ml+/-1071.0), NIND (2629.0 pg/ml+/-1669.0), acute peripheral OIND (2834.0 pg/ml+/-1118.) or chronic OIND (2764.0 pg/ml+/-659.7) were not significantly different, while they were significantly higher in acute central OIND (6218.0 pg/ml+/-3790.0; p<0.001 vs. MS and NIND; and p<0.05 vs. acute peripheral OIND). CONCLUSIONS: Our results strongly suggest that further investigation is warranted to elucidate the role of BAFF and APRIL in MS and that serum levels of BAFF and APRIL do not reflect CSF levels.

Raised intrathecal levels of APRIL and BAFF in patients with systemic lupus erythematosus: relationship to neuropsychiatric symptoms.

INTRODUCTION: The tumour necrosis factor (TNF) family ligands BAFF (B-cell activating factor of TNF family) and APRIL (a proliferation-inducing ligand) are essential for B-cell survival and function. Elevated serum levels of BAFF and APRIL have been reported earlier in patients with systemic lupus erythematosus (SLE). Since autoantibody formation in the central nervous system (CNS) is a distinct feature of neuropsychiatric SLE (NPSLE), we have investigated whether NPSLE is associated with an enhanced intrathecal production of APRIL and BAFF. METHODS: Levels of BAFF and APRIL in cerebrospinal fluid (CSF) and serum from healthy controls, SLE patients without CNS involvement, and patients with NPSLE were determined by enzyme-linked immunosorbent assay. Interleukin-6 (IL-6) levels were determined by an IL-6-specific bioassay. RESULTS: SLE patients had levels of APRIL in CSF that were more than 20-fold higher and levels of BAFF in CSF that were more than 200-fold higher than those of healthy controls. Separate analyses of SLE patients with and without CNS involvement revealed that NPSLE patients had enhanced levels of APRIL in CSF. BAFF and APRIL were likely produced locally in the CNS as CSF and serum levels did not correlate. Moreover, CSF levels of APRIL correlated with BAFF but not with IL-6, suggesting that APRIL and BAFF in the CNS are regulated together but that they are produced independently of IL-6. CONCLUSION: To our knowledge this is the first study to show elevated levels of BAFF and APRIL in CSF of SLE patients. APRIL was augmented in NPSLE patients compared with SLE patients without CNS involvement. APRIL and BAFF antagonists breeching the blood-brain barrier therefore could have beneficial effects on SLE patients, in particular patients with NPSLE.