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, GABABR, 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.
Highlights
Encephalitis is one type of brain inflammation caused by virus infection or autoimmune-mediated reactions
These results clearly indicate that this vesicle population isolated from cerebrospinal fluid (CSF) of antibody-positive Autoimmune encephalitis (AE) patients is enriched in exosomes
We found that miR-301a-5p, miR-21-5p, miR-34a-5p, miR-132-5p, and miR-29b-5p were significantly highly expressed in CSF exosomes in anti-N-methyl-d-aspartate receptor (NMDAR), GABABR, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-like 2 (CASPR2) AE patients when compared with healthy controls (p < 0.05), while miR-20a-5p was significantly lowly expressed in CSF exosomes (Fig. 3)
Summary
Encephalitis is one type of brain inflammation caused by virus infection or autoimmune-mediated reactions. Several types of encephalitis, including the classic paraneoplastic encephalitis syndromes, are immune mediated and often associated with autoantibodies against autoantigens, including neuronal surface proteins [1]. Several other autoantibodies against multiple neuronal autoantigens have been discovered in autoimmune encephalitis (AE) disease [3,4,5], including antigamma-aminobutyric acid-B receptor (GABABR) encephalitis, anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and anti-contactin-associated protein-like 2 (CASPR2) encephalitis. Ovarian teratoma is the most commonly associated tumor and is reported to be present in over half of adult females [8]. Half of adult cases with anti-GABAB receptor encephalitis have associated small cell lung carcinoma. Most adult cases with anti-AMPA receptor encephalitis are associated with neoplasms (including SCLC, thymoma, ovarian teratoma, and breast cancer) [9, 10]
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