Elevated Levels of NLRP3 in Cerebrospinal Fluid of Patients With Autoimmune GFAP Astrocytopathy.

Ying Luo,Baozhu Liu,Zhanhang Wang,Honghao Wang,Zheyi Zhou,Wei Yan,Jinyu Chen

doi:10.3389/fneur.2019.01019

Abstract

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy, a newly defined autoimmune encephalitis, is an antibody-mediated meningoencephalomyelitis. The pathogenesis of the disease is still unclear. Nod-like receptor protein 3 (NLRP3) inflammasome is a complex composed of a variety of proteins that recognizes a variety of ligands and ultimately leads to the development of inflammatory responses. This is important for infectious, inflammatory, and immune diseases. The aims of this study were to detect levels of cerebrospinal fluid (CSF) NLRP3 inflammasome and inflammatory factors in autoimmune GFAP astrocytopathy patients and to study the relationships between these profiles. Twenty autoimmune GFAP astrocytopathy patients, 17 viral meningoencephalitis (VM) patients, and 16 controls (CTLs) were recruited. The levels of NLRP3 inflammasomes, interleukin (IL)-1β, IL-6, and IL-17 were measured by enzyme-linked immunosorbent assay (ELISA). The Expanded Disability Status Scale (EDSS) score was used to assess the severity of clinical manifestations. The results showed that the levels of NLRP3 inflammasome and inflammatory cytokines (IL-1β, IL-6, IL-17) were significantly more elevated in CSF of patients with autoimmune GFAP astrocytopathy than that in CTLs. When compared with VM patients, significantly elevated NLRP3 inflammasome was found in GFAP astrocytopathy patients, while the levels of IL-1β, IL-6, and IL-17 were not different between the two groups. Significant positive correlations were found between NLRP3 inflammasome and inflammatory cytokines and they were all positively related to the severity of the disease. Moreover, we found that patients with positive anti-GFAP antibodies had higher levels of NLRP3 and inflammatory factors. And the severity of the disease was positively correlated with GFAP antibody titers. Taken together, the results suggested that NLRP3 inflammasome was involved in the pathogenesis of autoimmune GFAP astrocytopathy. It can be used to assess the severity of the disease or act as a new target for the therapy.

Highlights

As an important component of mature astrocyte intermediate filaments, glial fibrillary acidic protein (GFAP) plays prominent roles in maintaining the morphology of astrocytes, providing the blood-brain barrier (BBB) integrity and regulating synaptic function [1]
The results showed that patients with positive anti-GFAP antibody in cerebrospinal fluid (CSF) had higher Nod-like receptor protein 3 (NLRP3) inflammasome (p = 0.016, Figure 4A), IL-1β (p < 0.001, Figure 4B), and IL-17 (p = 0.029, Figure 4D), while there was no difference in IL-6 between the two subgroups (Figure 4C)
We found elevated levels of NLRP3 inflammasome and inflammatory cytokines (IL-1β, IL-6, IL17) in CSF in patients with autoimmune GFAP astrocytopathy

Summary

Introduction

As an important component of mature astrocyte intermediate filaments, GFAP plays prominent roles in maintaining the morphology of astrocytes, providing the blood-brain barrier (BBB) integrity and regulating synaptic function [1]. Autoimmune GFAP astrocytopathy, defined by Fang et al [2], is an antibody-mediated meningoencephalomyelitis. The main symptoms and signs include subacute headache, myelopathic symptoms, optic disc edema, tremor, ataxia, neck stiffness, autonomic instability, confusion, and progressive cognitive impairment [3,4,5], which were considerably similar to the symptoms of other autoimmune encephalitis. Lesions include the subcortical white matter, hypothalamus, brainstem, basal ganglia, cerebellum, and spinal cord. The characteristic MRI feature is brain linear perivascular radial gadolinium enhancement in white matter perpendicular to ventricle [6]. There is no accurate and uniform diagnostic criteria for Autoimmune GFAP astrocytopathy at present, and the detection of other coexisting neural autoantibodies in the same patient makes diagnosis difficult

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