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

Hopia, L; Thangarajh, Mathula; Khademi, Mohsen; Laveskog, Anna; Wallström, Erik; Svenungsson, Elisabet; Andersson, Magnus

doi:10.3109/03009742.2010.550900

Cited by 23 publications

(17 citation statements)

References 44 publications

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“…There was also a numerical increase in depression in one phase III belimumab study 9. BAFF is expressed in the central nervous system (CNS) of patients with multiple sclerosis (MS) and neuromyelitis optica (an MS spectrum disease with strong immunological overlap with SLE),21 22 has been reported in the CNS of patients with SLE and is more enhanced in those with neuropsychiatric involvement 23. Anxious behaviour has also been reported in an autoimmune BAFF transgenic murine model 24.…”

Section: Discussionmentioning

confidence: 98%

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

et al. 2015

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Section: Discussionmentioning

confidence: 98%

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

et al. 2015

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“…Although both are increased in neuropsychiatric lupus [12,14], only CSF BAFF is increased in untreated multiple sclerosis [19,20]. Another difference between BAFF and APRIL signaling in neuroinflammatory diseases is that both CSF and serum BAFF are elevated in neuro-Behcet’s disease [13], whereas only CSF BAFF is elevated in multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…Both are expressed by astrocytes [9,10], and also dendritic cells, macrophages, and monocytes [11]. In human cerebrospinal fluid (CSF) and serum, they are found in soluble form and often studied together in neuroinflammatory diseases [12-14]. The BAFF receptor (BAFF-R or BR3), one of three receptors to which BAFF binds [11], is the principal BAFF receptor [15] expressed by nearly all mature B cells [10].…”

Section: Introductionmentioning

confidence: 99%

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

Pranzatelli

Tate

McGee

et al. 2013

J Neuroinflammation

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BackgroundB-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder.ObjectiveTo 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.MethodsSoluble 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.ResultsThe 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).ConclusionsStriking 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.

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“…Treating these mice with a tolerogenic peptide (human first complementarity-determining region) down-regulated the expression of the pro-inflammatory mediators and ameliorated the memory impairment in the mice [ 95 ]. B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are B cell stimulation and survival molecules [ 96 ]. CSF APRIL, but not BLyS levels, in 28 patients with NPSLE were significantly higher than those of disease controls with non-SLE related neurological disorders [ 96 ].…”

Section: Mechanisms Of Cognitive Dysfunctionmentioning

confidence: 99%

Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus

Tay

Mak

2015

IJMS

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Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately 1–45.3 per 100,000 people worldwide. Although deaths as a result of active and renal diseases have been substantially declining amongst SLE patients, disease involving the central nervous system (CNS), collectively termed neuropsychiatric systemic lupus erythematosus (NPSLE), remains one of the important causes of death in these patients. Cognitive dysfunction is one of the most common manifestations of NPSLE, which comprises deficits in information-processing speed, attention and executive function, in conjunction with preservation of speech. Albeit a prevalent manifestation of NPSLE, the pathogenetic mechanisms of cognitive dysfunction remain unclear. Recent advances in genetic studies, molecular techniques, neuropathology, neuroimaging and cognitive science have gleaned valuable insights into the pathophysiology of lupus-related cognitive dysfunction. In recent years, a role for autoantibodies, molecular and cellular mechanisms in cognitive dysfunction, has been emerging, challenging our previous concept of the brain as an immune privileged site. This review will focus on the potential pathogenic factors involved in NPSLE, including anti-N-methyl-d-aspartate receptor subunit NR2A/B (anti-NR2A/B) antibodies, matrix metalloproteinase-9, neutrophil extracellular traps and pro-inflammatory mediators. Better understanding of these mechanistic processes will enhance identification of new therapeutic modalities to halt the progression of cognitive decline in SLE patients.

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

Abstract: 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.

Cited by 23 publications

References 44 publications

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

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

Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus

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