Selective localization of IgG from cerebrospinal fluid to brain parenchyma

Marlene Thorsen Mørch,Trevor Owens,Sofie Forsberg Sørensen,Reza Khorooshi,Nasrin Asgari

doi:10.1186/s12974-018-1159-8

Marlene Thorsen Mørch, Trevor Owens + Show 3 more

Open Access

https://doi.org/10.1186/s12974-018-1159-8

Copy DOI

Abstract

BackgroundEncounter of autoantibodies with specific antigens can lead to hypersensitivity reactions and pathology. In multiple sclerosis and neuromyelitis optica spectrum disease (NMOSD), immunoglobulin-G (IgG) deposition has been observed in pathological lesions in the central nervous system. The paradigmatic autoantibodies in NMOSD are specific for the water channel aquaporin-4, localized to astrocytic end-feet at the blood-brain barrier and ependymal cells at the cerebrospinal fluid-brain barrier. We have previously observed that IgG antibodies from NMO patients (NMO-IgG) access brain parenchyma from the cerebrospinal fluid and induce subpial and periventricular NMO-like lesions and blood-brain barrier breakdown, in a complement-dependent manner.ObjectiveTo investigate how IgG trafficking from cerebrospinal fluid to brain parenchyma can be influenced by injury.MethodsIgG from healthy donors was intrathecally injected into the cerebrospinal fluid via cisterna magna at 1, 2, 4, or 7 days after a distal stereotactic sterile needle insertion to the striatum.ResultsAntibody deposition, detected by staining for human IgG, peaked 1 day after the intrathecal injection and was selectively seen close to the needle insertion. When NMO-IgG was intrathecally injected, we observed complement-dependent NMO-like pathology (loss of aquaporin-4 and glial fibrillary acidic protein) proximal to the insertion site, with similar kinetics. A fluorescent tracer did not show the same distribution indicating IgG-selective localization.ConclusionThese findings suggest that IgG from cerebrospinal fluid localize selectively in brain parenchyma at the site of injury and pathogenic NMO-IgG induce astrocyte pathology at the same location.

Highlights

Inflammatory demyelinating diseases of the central nervous system (CNS) result in destruction of the myelin sheath and nerve fibers, which results in disability [1]
A fluorescent tracer did not show the same distribution indicating IgG-selective localization. These findings suggest that IgG from cerebrospinal fluid localize selectively in brain parenchyma at the site of injury and pathogenic Antibodies from NMO patients (NMO-IgG) induce astrocyte pathology at the same location
We have demonstrated that antibodies from NMO patients (NMO-IgG), with human complement that was intrathecally injected into the cerebrospinal fluid (CSF) via cisterna magna, induced NMO-like lesions with loss of AQP4 and glial fibrillary acidic protein (GFAP)

Summary

Introduction

Inflammatory demyelinating diseases of the central nervous system (CNS) result in destruction of the myelin sheath and nerve fibers, which results in disability [1]. We have demonstrated that antibodies from NMO patients (NMO-IgG), with human complement that was intrathecally injected into the CSF via cisterna magna, induced NMO-like lesions with loss of AQP4 and glial fibrillary acidic protein (GFAP). These lesions co-localized with deposition of human IgG and activated complement. In multiple sclerosis and neuromyelitis optica spectrum disease (NMOSD), immunoglobulin-G (IgG) deposition has been observed in pathological lesions in the central nervous system. The paradigmatic autoantibodies in NMOSD are specific for the water channel aquaporin-4, localized to astrocytic end-feet at the blood-brain barrier and ependymal cells at the cerebrospinal fluid-brain barrier. We have previously observed that IgG antibodies from NMO patients (NMO-IgG) access brain parenchyma from the cerebrospinal fluid and induce subpial and periventricular NMO-like lesions and blood-brain barrier breakdown, in a complement-dependent manner

Methods

Results

Conclusion