Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis

Yongang Li; Jiachen Gu; Youbing Mao; Xijia Wang; Zongshan Li; Xiaomin Xu; Huimin Chen; Yaxing Gui

doi:10.1007/s12035-021-02705-2

Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis

Mol Neurobiol. 2022 Apr;59(4):2441-2455. doi: 10.1007/s12035-021-02705-2. Epub 2022 Jan 27.

Authors

Yongang Li¹, Jiachen Gu², Youbing Mao³, Xijia Wang¹, Zongshan Li⁴, Xiaomin Xu⁴, Huimin Chen⁴, Yaxing Gui⁵

Affiliations

¹ Department of Neurology, The First People's Hospital of Wenling, Wenling, China.
² Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.86 Wujin Road, Shanghai, 200080, China.
³ Department of Neuroelectrophysiology, The First People's Hospital of Wenling, Wenling, China.
⁴ Department of Neurology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
⁵ Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.86 Wujin Road, Shanghai, 200080, China. YaxingGui@shsmu.edu.cn.

Abstract

Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( -) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABA_BR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( -) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.

Keywords: Autoimmune encephalitis (AE); Exosomes; Herpes simplex encephalitis (HSE); microRNAs.

MeSH terms

Animals
Anti-N-Methyl-D-Aspartate Receptor Encephalitis* / cerebrospinal fluid
Anti-N-Methyl-D-Aspartate Receptor Encephalitis* / etiology
Autoantibodies
Autoantigens
Encephalitis
Encephalitis, Herpes Simplex* / cerebrospinal fluid
Encephalitis, Herpes Simplex* / complications
Exosomes*
Hashimoto Disease
Humans
MicroRNAs* / genetics

Substances

Autoantibodies
Autoantigens
MicroRNAs

Supplementary concepts

Hashimoto's encephalitis