Transfer of patient’s peripheral blood mononuclear cells (PBMCs) disrupts blood–brain barrier and induces anti-NMDAR encephalitis: a study of novel humanized PBMC mouse model

Abstract

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood–brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. Methods In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients’ peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2−/−Il2rg−/−SirpαNODFlk2−/− mice. Results We found that engraftment of patients’ PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. Conclusions Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient’s lymphocytes.

Mechanisms of autoimmune encephalitis

“…Since the role of inflammatory and T cell mediated mechanisms is unclear in NMDAR encephalitis [107 ▪ ,113], several studies have focused on active immunization models [19–22,23 ▪ ,24–26]. In one model, mice were immunized using purified GluN1/GluN2B NMDAR embedded in liposomes, resulting in a fulminant encephalitis with several symptoms of the acute phase of NMDAR encephalitis, and antibodies against epitope regions other than the amino-terminal domain of the GluN1 subunit (main region involved in the human disease) [19].…”

Single-cell analyses of CSF and PBMCs from anti-NMDAR encephalitis patients reveals distinct characteristics of T cell subpopulations

“…In a mouse model of autoimmune encephalitis induced by repeated streptococcal infections, Th17 lymphocytes play a crucial role in the entry of autoantibodies into the central nervous system (CNS), sustained activation of microglia, and neurological deficits 21 . Another study established a humanized mouse model by transferring peripheral blood mononuclear cells (PBMCs) from NMDAR-E patients, showing infiltration of CD8 + T cells in the hippocampal region 22 . However, despite the observed infiltration of CD8 + T cells in brain tissues of NMDAR-E patients and animal models, no signs of neuronal apoptosis or necrosis have been found 17, 19 , suggesting that CD8 + T cells may not attack neurons through cytotoxic effects.…”