Abstract
BackgroundNeuropsychiatric manifestations are frequent in patients with systemic lupus erythematosus (SLE), yet the etiology and pathogenesis of brain damage in SLE remains unclear. Because the production of autoantibodies, formation and deposition of immunocomplexes are major serological characteristics of SLE, the elevated level of serum immunoglobulin may contribute to brain tissue injury of SLE. To testify this, in this study, we examined whether immunoglobulin G (IgG) in the serum of SLE patients affects the cellular functions in central nervous system and the potential mechanism.MethodsIn vivo intracerebral injection of SLE-serum in mouse was used to activate microglia and the production of pro-inflammatory cytokine was assessed by ELISA. Sera was divided into IgG and IgG depleted fractions, while IgG was further divided into Fc and Fab fragments to examine which part has an effect on microglia. Flow cytometry, immunofluorescence and quantitative PCR (qPCR) were used to verify the synergistic effect of B-cell activating factor (BAFF) on IgG stimulation of microglia.ResultsWe found that IgG in lupus sera can induce M1 activation of brain microglia following intraventricular injection into normal mice, and BAFF facilitates this process. In vitro, we identified that IgG bound to microglia through Fc rather than Fab fragments, and BAFF up-regulated the expression of Fc receptors (FcγR) on the surface of microglia, consequently, promote IgG binding to microglia.ConclusionOur results suggest that lupus serum IgG causes inflammatory responses of microglia by involving the Fc signaling pathway and the activity could be up-regulated by BAFF. Accordingly, disruption of the FcγR-mediated signaling pathway and blockade of microglia activation may be a therapeutic target in patients with neuropsychiatric lupus erythematosus.
Highlights
Neuropsychiatric manifestations are frequent in patients with systemic lupus erythematosus (SLE), yet the etiology and pathogenesis of brain damage in SLE remains unclear
Intraventricular injection of SLE‐serum induced M1‐polarized microglia activation To examine whether microglia were activated by intraventricular injection of SLE-serum, we performed immunohistological staining of ionized calcium binding adaptor molecule (Iba-1) on the brain slices of the cortex and hippocampus at 48 h after SLE-serum, healthy-serum, or artificial cerebrospinal fluid (ACSF) injection
B-cell activating factor (BAFF) in the SLE‐serum contributes to microglia activation We further examined whether the cytokines in SLE sera contribute to the microglia activation
Summary
Neuropsychiatric manifestations are frequent in patients with systemic lupus erythematosus (SLE), yet the etiology and pathogenesis of brain damage in SLE remains unclear. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high levels of autoantibody and damages in multiple organs, including central nervous system [1, 2]. Anti-ribosomal P-protein (anti-P) antibodies were associated with psychosis in some studies [10] These observations indicate that autoantibodies may play an important role in the brain damage involved in SLE, they only explain a minor proportion of several phenomena observed in the NPSLE patients. This may be due to the large variety of the antibodies in different SLE patients. There may be other operative mechanisms underlying the neuropathological changes of SLE
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