Abstract
BackgroundDevic’s neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial.MethodsTo explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgGAQP4+, NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats.ResultsWe showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively).In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-IgG-depleted condition. We did not find a major immune cell infiltration and microglial activation nor complement deposition in the central nervous system, in our model.ConclusionsWe establish a link between motor-deficit, NMO-like lesions and astrocytopathy mediated by intrathecal AQP4-IgG. Our study validates the concept of the intrinsic effect of autoantibody against surface antigens and offers a model for testing antibody and astrocyte-targeted therapies in NMO.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0577-8) contains supplementary material, which is available to authorized users.
Highlights
Devic’s neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury
To explore more widely the intrinsic immunopathogenic effect of AQP4-IgG and its functional and morphological consequence on astrocyte and on myelin and axons and to evaluate its clinical impact, we have developed a new animal model of NMO based on a chronic infusion of “physiological dose” of purified immunoglobulins (IgG) from NMO patient and healthy individual, into the cerebrospinal fluid (CSF) of live rats
IgGAQP4+ infused in the rat CSF diffused in the central nervous system (CNS) and induced astrocytopathy To validate our model of chronic infusion of autoantibody in rat CSF, we controlled the presence of human IgG in neural tissues of eight rats infused with IgGAQP4+ (NMOrats) and eight rats infused with IgGControl (Control-rats) on D7 and day 14 (D14)
Summary
Devic’s neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Devic’s neuromyelitis optica (NMO) is considered a primary astrocyte disease associated with central nervous system (CNS) inflammation, demyelination, and neuronal injury [1,2,3,4,5]. Autoantibodies against membrane antigen can act directly as receptor agonists/antagonists or modulate antigen density and trigger cell dysfunction, prior or in addition to complement activation or secondary inflammatory cell-mediated response [10]. These mechanisms probably take part, to some extent, in NMO. Recent detailed study of NMO pathology showed different lesion types, some associated to complement and immune cells infiltration but others with selective astrocyte loss in the absence of complement activation and granulocyte infiltration [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
