Cell-Free Mitochondrial DNA in the CSF: A Potential Prognostic Biomarker of Anti-NMDAR Encephalitis.

Yu Peng,Dong Zheng,Jun Zhang,Teng Ji,Xiaomei Zhang,Suyue Pan,Hong-Hao Wang,Hai-Ying Shen

doi:10.3389/fimmu.2019.00103

Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune inflammatory brain disease that can develop a variety of neuropsychiatric presentations. However, the underlying nature of its inflammatory neuronal injury remains unclear. Mitochondrial DNA (mtDNA) is recently regarded as a damage-associated molecular pattern molecule (DAMP) that can initiate an inflammatory response. In the presenting study, we aimed to evaluate the levels of cell-free mtDNA in cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and to determine a potential role of cell-free mtDNA in the prognosis of anti-NMDAR encephalitis. A total of 33 patients with NMDAR encephalitis and 17 patients with other non-inflammatory disorders as controls were included in this study. The CSF levels of cell-free mtDNA were measured by quantitative polymerase chain reaction (qPCR). Cytokines including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by ELISA. The modified Rankin scale (mRS) score was evaluated for neurologic disabilities. Our data showed that the CSF levels of cell-free mtDNA and inflammation-associated cytokines were significantly higher in the patients with anti-NMDAR encephalitis compared with those in controls. Positive correlations were detected between the CSF levels of cell-free mtDNA and mRS scores of patients with anti-NMDAR encephalitis at both their admission and 6-month follow up. These findings suggest that the CSF level of cell-free mtDNA reflects the underlying neuroinflammatory process in patients with anti-NMDAR encephalitis and correlates with their clinical mRS scores. Therefore, cell-free mtDNA may be a potential prognostic biomarker for anti-NMDAR encephalitis.

Highlights

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a newly recognized acute autoimmune encephalitis caused by anti-neuronal autoantibodies, which affects mainly children and young adult females [1, 2]
No significant correlation was shown between the cerebrospinal fluid (CSF) levels of cell-free Mitochondrial DNA (mtDNA) and three cytokines IL-6, IL-10, and TNF-α, or clinical outcome. In this cross-sectional study, we report for the first time the identification of cell-free mtDNA as a potential biomarker of mitochondrial damage in anti-NMDAR encephalitis
Our data demonstrating significantly increased CSF cell-free mtDNA suggests that cell-free mtDNA may participate in the pathogenesis of this disease, which in turn could reflect the severity of neurological impairment

Summary

Introduction

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a newly recognized acute autoimmune encephalitis caused by anti-neuronal autoantibodies, which affects mainly children and young adult females [1, 2]. The basal level of CSF cell-free mtDNA stays low and reflects the normal turnover of mtDNA in the brain, whereas elevated CSF levels of mtDNA were reported in patients with traumatic brain injury and multiple sclerosis. This indicates that mtDNA plays a mediatory role in sterile inflammatory responses [10, 11]. We investigated the cell-free mtDNA profile in the CSF of patients with anti-NMDAR encephalitis vs other non-inflammatory neurological disorders including peripheral nerve disease and hysteria. We further examined possible associations of their cell-free mtDNA profiles with the modified Rankin Scale (mRS) score and their cytokine profiles, including IL-6, IL-10, and TNF-α [12]

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