Lupus serum IgG induces microglia activation through Fc fragment dependent way and modulated by B-cell activating factor

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.

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

“…Consistently, we and others found that IgG-induced neuronal cytolysis occurs in pediatric OMS rather than adult OMS [6,7]. Notably, increased microglial activation is not specific to only OMS, since previous literatures have documented that serum IgG from patients with PD [12] or ALS [13] enhances the activation of microglia and the production of NO, and serum IgG from patients with SLE induced behavioral changes are mediated by microglial activation [14][15][16]. Moreover, several autoantibodies found in patients with OMS [40][41][42][43] also exist in other diseases, such as autoantibody against glycine receptor in progressive encephalomyelitis with rigidity and myoclonus [42,44] or autoantibody against glutamic acid decarboxylase in stiff-person syndrome [44].…”

“…The BCA assay (Pierce, Rockford, USA) was applied to determine IgG concentration. The Fab fragment of IgG was prepared by enzymatic digestion [16]. Pepsin (Sigma-Aldrich, St. Louis, MO, USA) was mixed with IgG at a ratio of 1:20, and then incubated at 37 °C for 6 h. Adjusting the solution pH to 7.4 to stop the digestion.…”

“…Moreover, the expression of microglial marker soluble CD14 and proinflammatory cytokines is enhanced in CSF from patients with pediatric OMS [10,11]. Additionally, serum IgG from patients or autoantibody existed in patients directly enhances microglial activation in PD [12], ALS [13] and SLE [14][15][16], or initially binds with astrocytes or neurons and further indirectly affects microglial activation [38,39]. Autoantibodies are also detectable in serum and CSF of children with OMS [25,26] and may be contained in serum IgG from children with OMS and NB in our study, although we did not identify these autoantibodies and autoantibodies include IgM besides IgG.…”

Serum IgG-induced microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

“…Moreover, the expression of microglial marker soluble CD14 and proinflammatory cytokines is enhanced in CSF from patients with pediatric OMS [10,11]. Additionally, serum IgG from patients or autoantibody existed in patients directly enhances microglial activation in PD [12], ALS [13] and SLE [14][15][16], or initially binds with astrocytes or neurons and further indirectly affects microglial activation [43,44]. Autoantibodies are also detectable in sera and CSF of children with OMS [25,26] and may be contained in serum IgG from children with OMS and NB in our study, although we did not identify these autoantibodies and autoantibodies include IgM besides IgG.…”

“…Notably, patients with pediatric OMS exhibit increased expression of a microglial marker and proinflammatory cytokines in cerebrospinal fluid (CSF) and some children with OMS are post-infectious [10,11]. Furthermore, serum IgG or autoantibody existed in patients enhances microglial activation in Parkinson disease (PD) [12], amyotrophic lateral sclerosis (ALS) [13] and systemic lupus erythematosus (SLE) [14][15][16]. Thus, it is reasonable to hypothesize that serum IgG from children with OMS and NB may impact the activation of microglia.…”