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High-throughput Flow Cytometry Cell-based Assay to Detect Antibodies to N-Methyl-D-aspartate Receptor or Dopamine-2 Receptor in Human Serum
Published on: November 23, 2013
Harnessing patient-derived antibodies-induced microglial complement 1q expression: Novel therapy for anti-NMDAR
Bingtian Xu1, Yunmeng Bai2, Zhuhe Liu1
1Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.
Abstract:
Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is the most prevalent autoimmune encephalitis caused by antibodies against the NMDAR subunit GluN1. Clinical evidence suggests that NMDARE is characterized by microglial activation, but the role of this activation remains unclear. In this study, single-nucleus RNA sequencing of the hippocampus from NMDARE mice revealed an upregulation of microglial complement 1q (C1q) levels. Clinically, we observed elevated C1q in the cerebrospinal fluid of NMDARE patients. Our studies showed that microglial cells express NMDAR, and antibodies from NMDARE patients act on microglia, inducing NMDAR internalization at the microglial membrane and triggering microglial C1q expression. Notably, silencing C1q attenuated the microglial activation induced by NMDAR antibodies, whereas C1q overexpression exacerbated this process. In vivo, C1q microglial knockout and knockdown in mice both showed reduced damage following NMDARE, while C1q overexpression in the hippocampus intensified pathological effects. Most promising is that neutralizing antibodies against C1q significantly mitigated injury in NMDARE mice. In summary, our findings highlight the therapeutic potential of inhibiting C1q to counteract NMDARE-induced injury.
Insights
Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) involves microglial activation. Targeting complement C1q, a key mediator, shows therapeutic potential for reducing NMDARE-induced brain injury.
Area of Science:
- Neuroimmunology
- Autoimmune Encephalitis
Background:
- Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is a prevalent autoimmune disorder.
- Microglial activation is observed in NMDARE, but its precise role is unclear.
Purpose of the Study:
- To investigate the role of microglial complement C1q in NMDARE pathogenesis.
- To explore C1q as a potential therapeutic target for NMDARE.
Main Methods:
- Single-nucleus RNA sequencing of NMDARE mouse hippocampus.
- Analysis of C1q levels in cerebrospinal fluid of NMDARE patients.
- In vitro and in vivo experiments involving NMDAR antibody treatment, C1q manipulation (silencing, overexpression, knockout), and C1q-neutralizing antibodies.
Main Results:
- Upregulation of microglial C1q in NMDARE mice and elevated C1q in NMDARE patients.
- NMDAR antibodies induce C1q expression in microglia via NMDAR internalization.
- C1q silencing reduced microglial activation and NMDARE-induced damage.
- C1q overexpression exacerbated NMDARE pathology.
- Neutralizing antibodies against C1q significantly mitigated NMDARE injury in vivo.
Conclusions:
- Microglial C1q plays a critical role in NMDARE pathogenesis.
- Inhibiting C1q represents a promising therapeutic strategy for NMDARE.
