Harnessing patient-derived antibodies-induced microglial complement 1q expression: Novel therapy for anti-NMDAR encephalitis.

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.