Abstract
Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system inflammatory disorders causing significant morbidities and mortality. The majority of NMOSD patients have autoimmunity against aquaporin-4 (AQP4), evidenced by seropositivity for autoantibodies against aquaporin-4 (AQP4–IgG). AQP4–IgG is pathogenic with neuroinflammation initiated upon binding of AQP4–IgG to astrocytic AQP4. Complement activation contributes to astrocytic cytotoxicity, neuroinflammation, and tissue necrosis in NMOSD, but the role of complement-independent mechanisms is uncertain. We studied the complement-independent pathogenic effects of AQP4–IgG by passive transfer of IgG from NMOSD patients to mice with breached blood–brain barrier (BBB). Mice, pretreated with bacterial proteins, received daily intraperitoneal injections of IgG purified from AQP4–IgG-seropositive NMOSD patients [IgG(AQP4+)], or IgG from AQP4–IgG-seronegative patients [IgG(AQP4−)] or healthy subjects [IgG(Healthy)] for 8 days. Motor function was tested by walking across narrow beams, and spinal cords were collected for immunofluorescent analysis. We found that human IgG infiltrated into cord parenchyma of mice with breached BBB without deposition of complement activation products. Spinal cord of mice that received IgG(AQP4+) demonstrated loss of AQP4 and glial fibrillary acidic protein (suggestive of astrocyte loss), decrease in excitatory amino acid transporter 2, microglial/macrophage activation, neutrophil infiltration, patchy demyelination, and loss in axonal integrity. Mice that received IgG(AQP4+) required longer time with more paw slips to walk across narrow beams indicative of motor slowing and incoordination. Our findings suggest that AQP4–IgG induces complement-independent cord pathologies, including astrocytopathy, neuroinflammation, demyelination, and axonal injuries/loss, which are associated with subtle motor impairments. These complement-independent pathophysiologies likely contribute to early NMOSD lesion development.
Highlights
Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) inflammatory demyelinating disorders (CNS IDD) characterized by recurrent episodes of acute optic neuritis, myelitis, and less frequently encephalitis
We observed marked loss of AQP4 and glia fibrillary acidic protein (GFAP) in IgG(AQP4+) mice, supporting that AQP4–IgG leads to astrocyte cytotoxicity in the absence of complement activation
These inflammatory mediators and chemokines may contribute to the marked microglial activation and proliferation, macrophage activation and mild neutrophil infiltration observed in IgG(AQP4+) mice in our study
Summary
Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) inflammatory demyelinating disorders (CNS IDD) characterized by recurrent episodes of acute optic neuritis, myelitis, and less frequently encephalitis. Severe NMOSD attacks, typically bilateral optic neuritis and AQP4–IgG-Mediated NMOSD Immunopathologies longitudinally extensive transverse myelitis can lead to permanent blindness, paraplegia, and even mortality [1]. Aquaporin-4 (AQP4) is the most abundant water channel in the mammalian CNS. It is highly expressed in the membrane of astrocytic endfeet at the interfaces between blood/ cerebrospinal fluid and brain parenchyma. Current evidence supports that AQP4– IgG is pathogenic and neuroinflammation is initiated upon binding of AQP4–IgG to astrocytic AQP4. In vitro studies suggest that binding of polyclonal AQP4–IgG to different epitopes of AQP4 triggers various outcomes which include AQP4 internalization and endolysosomal degradation [4], inflammatory cell infiltration [5], impairment of glutamate uptake [6, 7] and water flux [8], and breakdown of the blood–brain barrier (BBB) [9]
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